Spiro compounds or salts thereof and preventives/remedies for autoimmune diseases and AP-1 inhibitors containing the same

ABSTRACT

The spiro compounds of the present invention represented by the general formula:                    
     wherein A, R 2 , R 3 , R 4 , R 5 , R 6  and n are as defined in the specification, exhibit an AP-1 activity inhibitory action and, based on the AP-1 inhibitory action, suppresses the expression of a wide variety of genes and are useful as an agent for treating and preventing autoimmune diseases with lessoned side reactions.

TECHNICAL FIELD

The present invention relates to novel spiro compounds or salts thereof that inhibit the activity of a transcription factor AP-1 and are useful as agents for treating autoimmune diseases, agents for preventing and/or treating autoimmune diseases and an AP-1 inhibitor containing the same.

BACKGROUND ART

Up to today, therapeutic drugs for many diseases have been developed to control the functions of proteins such as enzymes and receptors. For example, for treating inflammatory diseases such as rheumatoid arthritis, etc., cycloxygenase synthesizing prostaglandins from arachidonic acid or 5-lipoxygenase synthesizing leucotrienes have been taken as a target, and a number of non-steroidal antiinflammatory drugs such as indomethacin have been developed and put to therapeutic uses (J. Pharm. Sci., Vol. 73, Pages 579-589, 1984). Inflammatory cytokines such as interleukins (IL)-1 and IL-6 and tumor necrotic factor (TNF) have attracted intention as amplifying or aggravating factors in inflammatory reaction. As agents for regulating the functions of these proteins, monoclonal antibodies for respective proteins (Arthritis Rheum., Vol. 36, Pages 1681-1690, 1993), low molecular weight cytokine production inhibitors (Ann. Rep. Med. Chem., Vol. 27, Pages 209-218, 1992), etc. are being developed. Further, the use of antibodies for those cytokine receptors is also being attempted clinically (Rheumatism, Vol. 37, No. 2, Page 174, 1997).

In the diseases caused by a quantitative abnormality of functional proteins existing in cells or on cell membranes or of functional molecules secreted from cells, however, it is considered that a therapy in the true sense is to regulate the quantity of transcription of functional molecule gene and thereby normalize the quantity of expression rather than to inhibit the activity of the functional molecules. It is known that not only the quantitative abnormalities of the above-mentioned inflammatory cytokines and lipid mediators synthesized from arachidonic acid but also the quantitative abnormalities of many functional proteins such as adhesion molecules and matrix metallo proteinases take part in the cause of autoimmune diseases such as rheumatoid arthritis and chronic inflammatory diseases (N. Engl. J. Med., Vol. 322, Pages 1277-1289, 1990). Although gene expression and production of these functional proteins are regulated by a plurality of transcription factors, it is known that the promoter region of a majority of such genes commonly involves a consensus sequences of transcription factor AP-1 (TRE sequence). Further, it has been reported that expression of some of these functional proteins is regulated by binding of AP-1 to the promoter region (Nature, Vol. 337, Pages 661-663, 1989).

A living body exhibits various defensive reactions against outer stimulation and attack, and shows immune responses and inflammatory reactions.

Cellular and molecular analyses of such reactions have made a surprising progress in the recent years, due to which it has become apparent that gene expression and production of proteins to make sure the physiological functions was induced the stimulation in all the cells constituting a living body.

The immune responses and inflammatory reactions are amplified and regulated by the interaction of these genes including inflammatory cytokines such as IL-1 and TNFα, cell surface molecules such as cell-adhesion molecules and various cytokine receptors and enzymes such as matrix metallo-proteinases. On the other hand, autoimmune diseases typified by rheumatoid arthritis and other intractable chronic inflammatory diseases are considered caused by an excessive immunity and inflammatory reactions. That is, it is prospected that, in these inflammatory diseases, such a wide variety of genes directly relating to the etiology of disease are expressed in an excessive quantity, so that a mere inhibition or control of only one genetic product (protein) is incapable of realizing a sufficient therapy (radical therapy).

At the present time, non-steroidal anti-inflammatory agents and steroidal agents are used for the pharmaceutical treatment of chronic inflammatory diseases such as rheumatoid arthritis. Non-steroidal anti-inflammatory agents such as indomethacin and the like inhibit cycloxygenase and thereby suppress the production of lipid mediators such as prostaglandin E₂ and the like. However, such a treatment is not sufficient as a radical therapy because the use of these drugs is to suppress only one inflammatory mediator, cycloxygenase, and the effect thereof is nothing but an expectation of a conservative treatment. On the other hand, steroidal agents are known to exhibit regulating effect at the stage of expression of gene through intermediation of a glucocorticoid receptor, and it has actually been reported that these agents inhibit the activity of transcription factor AP-1 and thereby suppress the production of cytokines and other proteins (Cell, Vol. 62, Pages 1189-1204, 1990). Although effectiveness of such steroidal agents are sufficiently recognized, the use of such steroidal agents is restricted by the hormonal and side effects thereof, and they cannot be administered over a long period of time. Especially, the inflammatory diseases such as autoimmune diseases are generally chronic and require a long-term therapy, so that drugs having intense side effects cannot be used at least at the present time.

Thus, it has been desired to develop an agent for treating and/or preventing autoimmune diseases which inhibits AP-1 activity and can suppress the expression of a wide variety of genes through inhibiting AP-1 activity thereof, with lessened side reactions.

DISCLOSURE OF THE INVENTION

The present inventors have conducted extensive studies with the aim of developing an agent for treating and/or preventing autoimmune diseases which inhibits AP-1 activity and can suppress the expression of a wide variety of genes through inhibiting AP-1 activity thereof, with lessened side reactions. As a result, it has been found-that spiro compounds having a spiro ring skeleton represented by the following general formula [1]:

wherein A is a group of the following general formula:

wherein R^(1a) represents hydrogen atom, halogen atom, cyano group, nitro group, an unprotected or protected carboxyl group, an unprotected or protected hydroxyl group, or an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl, aralkyl, alkoxy, aryloxy, acyl, alkoxycarbonyl, aryloxycarbonyl, carbamoyl, amino or heterocyclic group; and Y⁰ represents oxygen atom, sulfur atom, an unsubstituted or substituted imino group, carbonyl group, methylene group, vinylene group, sulfinyl group, sulfonyl group or group —CH(OH)—; or a group of the following general formula:

wherein R^(1c) and R^(1d), same or different, each represents hydrogen atom, halogen atom, cyano group, nitro group, an unprotected or protected carboxyl group, an unprotected or protected hydroxyl group, mercapto group, or an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl, aralkyl, alkoxy, aryloxy, acyl, alkoxycarbonyl, aryloxycarbonyl, carbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, amino or heterocyclic group;

or a group of the following general formula:

wherein R^(1e) and R^(1f), same or different, each represents halogen atom, cyano group, nitro group, an unprotected or protected carboxyl group, an unprotected or protected hydroxyl group, or an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl, aralkyl, alkoxy, aryloxy, acyl, alkoxycarbonyl, aryloxycarbonyl, carbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, amino or heterocyclic group; or a group of the following general formula:

wherein R^(1g) represents an unsubstituted or substituted heterocyclic group;

R² represents hydrogen atom or an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, acyl, aryl, aralkyl, alkylsulfonyl, arylsulfonyl or heterocyclic group; R³ and R⁴, same or different, each represents hydrogen atom, halogen atom, cyano group, an unprotected or protected carboxyl group, an unprotected or protected hydroxyl group, or an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, acyl, alkoxycarbonyl, aryl, amino, alkylamino, acylamino, carbamoyl or heterocyclic group or R³ and R⁴, taken conjointly, represent an oxo group; R⁵ and R⁶, same or different, each represents hydrogen atom, halogen atom, cyano group, an unprotected or protected carboxyl group, an unprotected or protected hydroxyl group, or an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, acyl, alkoxycarbonyl, aryl, amino, alkylamino, acylamino, carbamoyl or heterocyclic group or R⁵ and R⁶, taken conjointly with the terminal carbon atom to which R⁵ and R⁶ are combined, represent an alkenyl group; and n represents 0, 1 or 2;

spiro compounds represented by the general formula [1] wherein A is a group represented by the following general formula:

wherein R^(1h) represents a group of the following general formula:

R¹¹—Y²—

wherein R¹¹ represents hydrogen atom, halogen atom, cyano group, an unprotected or protected carboxyl, hydroxyl or mercapto group or an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl, alkoxy, alkylthio, alkylsulfonyl, arylsulfonyl, sulfamoyl, acyl, acyloxy, alkoxycarbonyl, aryloxycarbonyl, amino, carbamoyl, carbamoyloxy or heterocyclic group; and Y² represents methylene group, an unsubstituted or substituted imino group, carbonyl group or sulfonyl group; or a group of the following general formula:

R¹²—(E¹)_(j)—

wherein E¹ represents amino acid residue; R¹² represents hydrogen atom or a protecting group for amino group; and j represents 2 or 3;

R² represents hydrogen atom, an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, acyl, aryl, arylsulfonyl, alkylsulfonyl, aralkyl or heterocyclic group;

R³ and R⁴, taken conjointly, represent an oxo group; R⁵ represents hydrogen atom; R⁶ represents a group of the following general formula:

wherein R¹³ represents hydrogen atom, halogen atom, an unprotected or protected hydroxyl, hydroxyamino, amino, alkylamino, arylamino, acylamino, alkoxycarbonylamino, arylsulfonylamino or alkylsulfonylamino group, an unsubstituted or substituted alkyl, aryloxy, aralkyloxy, alkylthio, alkoxy, aryl or heterocyclic group, or a group of the following general formula:

R¹⁴—(E²)_(l)—

wherein E² represents amino acid residue; R¹⁴ represents hydroxyl group or amino group; and l represents 1, 2 or 3; k represents 1, 2 or 3; and n represents 0, 1 or 2;

spiro compounds represented by general formula [1] wherein A represents a group of the following general formula:

wherein R^(1h) represents a group of the following general formula:

R¹⁵—Y³—

wherein R¹⁵ represents hydrogen atom, halogen atom, cyano group, an unprotected or protected carboxyl, hydroxyl or mercapto group, or an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl, alkoxy, alkylthio, alkylsulfonyl, arylsulfonyl, sulfamoyl, acyl, acyloxy, alkoxycarbonyl, aryloxycarbonyl, amino, carbamoyl, carbamoyloxy or heterocyclic group; and Y³ represents methylene group, an unsubstituted or substituted imino group, carbonyl group or sulfonyl group; or

a group of the following general formula:

R¹⁶—(E³)_(s)—

wherein E³ represents amino acid residue; R¹⁶ represents hydrogen atom or a protecting group for amino group; and s represents 2 or 3;

R² represents hydrogen atom, an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, acyl, aryl, arylsulfonyl, alkylsulfonyl, aralkyl or heterocyclic group; R³ and R⁴, same or different, each represents hydrogen atom, halogen atom, cyano group, an unprotected or protected hydroxyl group or an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, acyl, alkoxycarbonyl, aryl, amino, alkylamino, acylamino, carbamoyl or heterocyclic group; or a group of the following general formula:

—CO—(E⁴)_(t)—R¹⁸

wherein E⁴ represents amino acid residue; R¹⁸ represents hydroxyl group or amino group; and t represents 1, 2 or 3; R⁵ and R⁶, same or different, each represents hydrogen atom, halogen atom, cyano group, an unprotected or protected carboxyl group, an unprotected or protected hydroxyl group, an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, acyl, alkoxycarbonyl, aryl, amino, alkylamino, acylamino, carbamoyl or heterocyclic group; and n represents 0, 1 or 2; and salts of the above-mentioned spiro compounds inhibit the activity of transcription factor AP-1 and are useful as an agent for preventing and/or treating autoimmune diseases. Based on this finding, the present invention has been accomplished.

The compounds of the present invention inhibit the activity of transcription factor AP-1. That is to say, the compound of the present invention inhibits the transcription of DNAs having a TRE alignment in the promoter region thereof. Thereby, it is possible to inhibit the production of proteins corresponding to the gene in genes having TRE sequence. Accordingly, the compounds of the present invention can suppress the expression of genes of cytokines group such as IL-1β, IL-2, IL-3, IL-8, TNFα, granulocyte-macrophage colony stimulating factor (GM-CSF), monocyte chemoattractant protein 1 (MCP-1), etc., MMPs such as collagenase (MMP-1), stromelycin (MMP-3), collagenase IV (MMP-9), etc., cell surface molecules such as immunoglobulins, major histocompatibility complex (MHC) class II, vascular cell adhesion molecule 1 (VCAM-1), fibroblast growth factor (FGF) receptor, etc., growth factors such as monocyte growth factor, insulin-related growth factor (IGF), nerve growth factor (NGF), etc., and metallothionein, collagen, osteocarcin, osteopontin, amyloid precursor protein, apolipoprotein-1, etc. Accordingly, the compounds of the present invention can prevent and/or treat the diseases is related to these genes.

As the diseases is related these genes, for example, collagen diseases (rheumatoid arthritis, systemiclupus erythematosus, general scleroderma, rheumatic fever, multiple myositis, periarteritis nodosa, Sjögren's syndrome and Behçet's syndrome), idiopathic ulcerative colitis, glomerulonephritis, various autoimmune diseases such as autoimmune hemolytic anemia and the like, active chronic hepatitis, osteoarthritis, gout, atherosclerosis, psoriasis, atopic dermatitis, lungal diseases accompanied by granuloma such as interstitial pneumonia, various meningitises, Alzheimer's disease, and other intractable chronic inflammatory diseases can be referred to.

Hereunder, the compounds of the present invention will be detailed.

Unless otherwise referred to, the term “halogen atom” used in this specification means fluorine atom, chlorine atom, bromine atom and iodine atom; the term “alkyl group” means a straight or branched chain C₁₋₁₂ alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl and the like; the term “alkenyl group” means a straight or branched chain C₂₋₁₂ alkenyl group such as vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, hexenyl, heptenyl, octenyl and the like; the term “cycloalkyl group” means a C₃₋₆ cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like; the term “aryl group” means a group such as phenyl, tolyl, naphthyl and the like; the term “alkoxy group” means a straight or branched chain C₁₋₁₂ alkoxy group such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy and the like; the term “alkoxyimino group” means a straight or branched chain C₁₋₁₂ alkoxyimino group such as methoxyimino, ethoxyimino and the like; the term “alkoxycarbonylamino group” means a straight or branched chain C₁₋₁₂ alkoxycarbonylamino group such as methoxycarbonylamino, ethoxycarbonylamino, n-propoxycarbonylamino, isopropoxycarbonylamino, n-butoxycarbonylamino, isobutoxycarbonylamino, sec-butoxycarbonylamino, tert-butoxycarbonylamino, pentyloxycarbonylamino, hexyloxycarbonylamino, heptyloxycarbonylamino, octyloxycarbonylamino and the like; the term “arylsulfonylamino group” means an aryl-SO₂NH— group such as phenylsulfonylamino, naphthylsulfonylamino and the like; the term “alkylsulfonylamino group” means a straight or branched chain C₁₋₁₂ alkylsulfonylamino group such as methylsulfonylamino, ethylsulfonylamino, n-propylsulfonylamino, isopropylsulfonylamino, n-butylsulfonylamino, isobutylsulfonylamino, sec-butylsulfonylamino, tert-butylsulfonylamino, pentylsulfonylamino, hexylsulfonylamino, heptyl-sulfonylamino, octylsulfonylamino and the like; the term “aryloxy group” means a group represented by aryl-O— such as phenoxy, tolyloxy, naphthoxy and the like; the term “aryloxycarbonyl group” means a group represented by aryl-O—CO— such as phenoxycarbonyl, naphthoxycarbonyl and the like; the term “arylamino group” means a group such as phenylamino, naphthylamino and the like; the term “alkylamino group” means a mono- or di-C₁₋₁₂ alkylamino group such as methylamino, ethylamino, propylamino, butylamino, pentylamino, hexylamino, heptylamino, octylamino, dimethylamino, diethylamino, methylethylamino, dipropylamino, dibutylamino, dipentylamino, dihexylamino, diheptylamino, dioctylamino and the like; the term “aralkyl group” means an ar-C₁₋₁₂-alkyl group such as benzyl, phenethyl, 4-methylbenzyl, naphthylmethyl and the like; the term “alkylidene group” means a C₁₋₁₂ alkylidene group such as methylene, ethylidene, propylidene, isopropylidene, butylidene, hexylidene, octylidene and the like; the term “aralkyloxy group” means an ar-C₁₋₁₂-alkyloxy group such as benzyloxy, phenethyloxy, 4-methylbenzyloxy, naphthylmethyloxy and the like; the term “aralkyloxycarbonyl group” means an ar-C₁₋₁₂-alkyloxycarbonyl group such as benzyloxycarbonyl, phenethyloxycarbonyl, 4-methylbenzyloxycarbonyl, naphthylmethyloxycarbonyl and the like; the term “aralkylcarbonyloxy group” means an ar-C₁₋₁₂-alkylcarbonyloxy group such as benzylcarbonyloxy, phenethylcarbonyloxy, 4-methylbenzylcarbonyloxy, naphthylmethylcarbonyloxy and the like; the term “aralkylcarbonyl group” means a group represented by aralkyl-CO— wherein aralkyl is as defined above; the term “acyl group” means acyl groups including C₂₋₁₂ alkanoyl groups such as formyl, acetyl, propionyl and the like, aralkylcarbonyl groups such as benzylcarbonyl and the like, aroyl groups such as benzoyl, naphthoyl and the like and heterocycle-carbonyl groups such as nicotinoyl, thenoyl, pyrrolidinocarbonyl, furoyl and the like; the term “acyloxy group” means a group represented by acyl-O— wherein acyl is as defined above; the term “acylamino group” means a C₁₋₆ acylamino group such as formylamino, acetylamino, propionylamino, butyrylamino and the like; the term “aralkyloxycarbonyl group” means an ar-C₁₋₁₂-alkyloxy-CO— group such as benzyloxycarbonyl, phenethyloxycarbonyl, 4-methylbenzyloxycarbonyl, naphthylmethyloxycarbonyl and the like; the term “cyclic amino group” means a cyclic amino group which may be any of saturated and unsaturated cyclic amino groups and may contain at least one heteroatom such as nitrogen atom, oxygen atom, sulfur atom or the like and a carbonyl carbon in the ring thereof and may be any of monocyclic, bicyclic and tricyclic amino groups, of which more specific examples include saturated or unsaturated, monocyclic, 3- to 7-membered cyclic amino groups containing one nitrogen atom such as aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl, pyrrolin-1-yl, pyrrol-1-yl, dihydropyridin-1-yl, piperidino, dihydroazepin-1-yl, perhydroazepin-1-yl and the like; saturated or unsaturated, monocyclic, 3- to 7-membered cyclic amino groups containing two nitrogen atoms such as imidazol-1-yl, imidazolidin-1-yl, imidazolin-1-yl, pyrazolidin-1-yl, piperazin-1-yl, 1,4-dihydropyrazin-1-yl, 1,2-dihydropyrimidin-1-yl, perhydropyrazin-1-yl, homopiperazin-1-yl and the like; saturated or unsaturated, monocyclic, 3- to 7-membered cyclic amino groups containing three or more nitrogen atoms such as 1,2,4-triazol-1-yl, 1,2,3-triazol-1-yl, 1,2-dihydro-1,2,4-triazin-1-yl, perhydro-S-triazin-1-yl and the like; saturated or unsaturated, monocyclic, 3- to 7-membered cyclic amino groups containing 1 to 4 heteroatoms selected from the group consisting of oxygen atom and sulfur atom in addition to nitrogen atom such as oxazolidin-3-yl, isoxazolidin-2-yl, morpholino, 1,3-oxazolidin-3-yl, thiazolidin-1-yl, isothiazolidin-1-yl, thiomorpholino, homothiomorpholin-1-yl, 1,2,4-thiadiazolin-2-yl and the like; saturated or unsaturated, bicyclic or tricyclic cyclic amino groups such as isoindolin-2-yl, indolin-1-yl, 1H-indazol-1-yl, purin-7-yl, tetrahydroquinolin-1-yl and the like; and spiro or crosslinked, saturated or unsaturated, 5- to 12-membered cyclic amino groups such as 5-azaspiro[2,4]heptan-5-yl, 2,8-diazabicyclo[4.3.0]-nonan-8-yl, 3-azabicyclo[3.1.0]hexan-3-yl, 2-oxa-5,8-diazabicyclo[4.3.0]nonan-8-yl, 2,8-diazaspiro[4,4]-nonan-2-yl, 7-azabicyclo[2.2.1]heptan-7-yl and the like; the term “heterocyclic group” means a 4- to 7-membered or fused heterocyclic group containing at least one heteroatom selected from the group consisting of oxygen atom, nitrogen atom and sulfur atom such as azetidinyl, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, furazanyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiazidiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, thiatriazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, piperidinyl, piperazinyl, pyranyl, morpholinyl, 1,2,4-triazinyl, benzothienyl, naphthothienyl, benzofuryl, isobenzofuryl, chromenyl, indolidinyl, isoindolyl, indolyl, indazolyl, purinyl, quinolyl, isoquinolyl, phthalazinyl, naphthylidinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, isochromanyl, chromanyl, indolinyl, isoindolinyl, benzoxazolyl, triazolopyridyl, tetrazolopyridazinyl, tetrazolopyrimidinyl, thiazolopyridazinyl, thiadiazolopyridazinyl, triazolopyridazinyl, benzimidazolyl, benzothiazolyl, 1,2,3,4-tetrahydroquinolyl, imidazo[1,2-b][1,2,4]triazinyl, quinuclidinyl and the like; the term “alkanoyl group” means a C₂₋₁₂ alkanoyl group such as acetyl, propionyl and the like; the term “aroyl group” means an aroyl group such as benzoyl, naphthoyl and the like; the term “heterocycle-carbonyl group” means a group represented by heterocycle-CO— wherein heterocycle is as defined above); the term “alkylthio group” means a straight or branched chain C₁₋₁₂ alkylthio group such as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, hexylthio, heptylthio, octylthio and the like; the term “alkylsulfinyl group” means a straight or branched chain C₁₋₁₂ alkylsulfinyl group such as methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl, n-butylsulfinyl, isobutylsulfinyl, sec-butylsulfinyl, tert-butylsulfinyl, pentylsulfinyl, hexylsulfinyl, heptylsulfinyl, octylsulfinyl and the like; the term “alkylsulfonyl group” means a straight or branched chain C₁₋₁₂ alkylsulfonyl group such as methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, pentylsulfonyl, hexylsulfonyl, heptylsulfonyl, octylsulfonyl and the like; the term “arylsulfonyl group” means, for example, phenylsulfonyl group or naphthylsulfonyl group; the term “alkylsulfonyloxy group” means a straight or branched chain C₁₋₁₂ alkylsulfonyloxy group such as methylsulfonyloxy, ethylsulfonyloxy, n-propylsulfonyloxy, isopropylsulfonyloxy, n-butylsulfonyloxy, isobutylsulfonyloxy, sec-butylsulfonyloxy, tert-butylsulfonyloxy, pentylsulfonyloxy, hexylsulfonyloxy, heptylsulfonyloxy, octylsulfonyloxy and the like; the term “arylsulfonyloxy group” means a group such as phenylsulfonyloxy, naphthylsulfonyloxy and the like; the term “alkoxycarbonyl group” means a straight or branched chain C₁₋₁₂ alkyloxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and the like; and the term “alkoxycarbonyloxy group” means a straight or branched chain C₁₋₁₂ alkyloxycarbonyloxy group such as methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy and the like.

As R^(1a), R^(1b), R^(1c), R^(1d), R^(1e), R^(1f), R^(1g), R^(1aa), R^(1ba), R^(1ca), R^(1da), R^(1ea), R^(1fa), R^(1la), R^(aa), R^(bb), R^(cc), R^(dd), R^(ee), R^(ff), R^(aaa), R^(bbb), R^(ccc), R^(ddd), R^(eee), R^(fff), R², R^(2a), R³, R⁴, R⁵, R⁶, R¹¹, R¹³, R^(13a), R^(13aa), R¹⁵, R^(15a), Y, Y⁰, Y², Y³ and the substituents used in the formulas of production processes, for example, halogen atom, cyano group, nitro group, sulfo group, mercapto group, an unprotected or protected carboxyl group, an unprotected or protected hydroxyl and hydroxyimino groups, an unprotected or protected amino group, an unprotected or protected imino group, an unsubstituted or substituted alkyl, alkoxy, alkoxycarbonyl, alkoxyimino, acyl, acyloxy, carbamoyl, carbamoyloxy, aralkylcarbonyloxy, aryl, aryloxycarbonyl, aralkyloxycarbonyl, cycloalkyl, alkenyl, aralkyl, alkylthio, alkylsulfonyl, alkylsulfonyloxy, alkylidene and heterocyclic groups, an unprotected or protected cyclic amino, aminosulfonyl, aminosulfinyl, alkoxycarbonylamino and alkylamino groups can be referred to. If desired, these groups may be substituted with at least one of these substituents. As the substituted alkyl group in R^(1b), R^(1ba), R^(bb) and R^(bbb), the same groups as above can be referred to, and they are substituted with at least one of these substituents.

The protecting groups for carboxyl group which can be used include all the groups conventionally usable as a protecting group for carboxyl group. As examples thereof, there can be referred to alkyl groups such as methyl, ethyl, n-propyl, iso-propyl, 1,1-dimethylpropyl, n-butyl, tert-butyl and the like; aryl groups such as phenyl, naphthyl and the like; aralkyl groups such as benzyl, diphenylmethyl, trityl, p-nitrobenzyl, p-methoxybenzyl, bis(p-methoxyphenyl)methyl and the like; acyl-alkyl groups such as acetylmethyl, benzoylmethyl, p-nitrobenzoylmethyl, p-bromobenzoylmethyl, p-methanesulfonylbenzoylmethyl and the like; oxygen-containing heterocyclic groups such as 2-tetrahydropyranyl, 2-tetrahydrofuranyl and the like; halogeno-alkyl groups such as 2,2,2-trichloroethyl and the like; alkylsilylalkyl groups such as 2-(trimethylsilyl)ethyl and the like; acyloxyalkyl groups such as acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl and the like; nitrogen-containing heterocycle-alkyl groups such as phthalimidomethyl, succinimidomethyl and the like; cycloalkyl groups such as cyclohexyl and the like; alkoxy-alkyl groups such as methoxymethyl, methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl and the like; ar-alkoxy-alkyl groups such as benzyloxymethyl and the like; alkylthio-alkyl groups such as methylthiomethyl, 2-methylthioethyl and the like; arylthio-alkyl groups such as phenylthiomethyl and the like; alkenyl groups such as 1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl and the like; and substituted silyl groups such as trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl, tert-butylmethoxyphenylsilyl and the like.

The protecting groups for amino group which can be used include all the groups conventionally usable as a protecting group for amino group. As examples thereof, there can be referred to acyl groups such as trichloroethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl, p-nitrobenzylcarbonyl, o-bromobenzyloxycarbonyl, (mono-, di-, tri-)chloroacetyl, trifluoroacetyl, phenylacetyl, formyl, acetyl, benzoyl, tert-amyloxycarbonyl, tert-butoxycarbonyl, p-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 4-(phenylazo)benzyloxycarbonyl, 2-furfuryloxycarbonyl, diphenylmethoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, phthaloyl, succinyl, alanyl, leucyl, 1-adamantyloxycarbonyl, 8-quinolyloxycarbonyl and the like; aralkyl groups such as benzyl, diphenylmethyl, trityl and the like; arylthio groups such as 2-nitrophenylthio, 2,4-dinitrophenylthio and the like; alkyl- and aryl-sulfonyl groups such as methanesulfonyl, paratoluenesulfonyl and the like; dialkylamino-alkylidene groups such as N,N-dimethylaminomethylene and the like; aralkylidene groups such as benzylidene, 2-hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene, 2-hydroxy-1-naphthylmethylene and the like; nitrogen-containing heterocyclic alkylidene groups such as 3-hydroxy-4-pyridylmethylene and the like; cycloalkylidene groups such as cyclohexylidene, 2-ethoxycarbonylcyclohexylidene, 2-ethoxycarbonylcyclopentylidene, 2-acetylcyclohexylidene, 3,3-dimethyl-5-oxycyclohexylidene and the like; diaryl- and diaralkylphosphoryl groups such as diphenylphosphoryl, dibenzylphosphoryl and the like; oxygen-containing heterocyclic alkyl groups such as 5-methyl-2-oxo-2H-1,3-dioxol-4-yl-methyl and the like; and substituted silyl groups such as trimethylsilyl and the like.

The protecting groups for hydroxyl group which can be used include all the groups conventionally usable as a protecting group for hydroxyl group. As examples thereof, there can be referred to acyl groups such as benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, isobutyloxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl, 2-(trimethylsilyl)-ethoxycarbonyl, 2-(phenylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphonio)ethoxycarbonyl, 2-furfuryloxycarbonyl, 1-adamantyloxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, S-benzylthiocarbonyl, 4-ethoxy-1-naphthyloxycarbonyl, 8-quinolyloxycarbonyl, acetyl, formyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenyloxyacetyl, pivaloyl, benzoyl and the like; alkyl groups such as methyl, tert-butyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl and the like; alkenyl groups such as allyl and the like; aralkyl groups such as benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, diphenylmethyl, trityl and the like; oxygen-containing and sulfur-containing heterocyclic groups such as tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiopyranyl and the like; alkoxy-alkyl groups such as methoxymethyl, methylthiomethyl, benzyloxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, 1-ethoxyethyl and the like; alkyl- and aryl-sulfonyl groups such as methanesulfonyl, paratoluenesulfonyl and the like; and substituted silyl groups such as trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl, tert-butylmethoxyphenylsilyl and the like.

The term “amino acid residue” means an —NH(CHR)_(Z)CO— part (R is an amino acid side chain, and Z is an integer of 1 to 6) which appears when an amino acid is introduced into a protein molecule or a peptide molecule while forming a peptide bonding with loss of a water molecule. Herein, the term “amino acid” means a compound having a carboxyl group and an amino group in one molecule such as glycine, alanine, valine, leucine, isoleucine, serine, threonine, asparagine, aspartic acid, glutamine, glutamic acid, lysine, alginine, histidine, methionine, thyrosine, phenylalanine, tryptophane, proline, cysteine, homocysteine, β-alanine, γ-aminobutyric acid, ornithine, 3,4-dihydroxyphenylalanine and the like.

As the salt of the compound of general formula [1], usually known salts formed at the site of basic group such as amino group and the like and at the site of acidic group such as hydroxyl or carboxyl group and the like can be referred to. As the salt formed at the site of a basic group, for example, salts of a mineral acid such as hydrochloric acid, hydrobromic acid, sulfuric acid and the like; salts of an organic acid such as tartaric acid, formic acid, citric acid, trichloroacetic acid, trifluoroacetic acid and the like; and salts of a sulfonic acid such as methanesulfonic acid, benzenesulfonic acid, paratoluenesulfonic acid, mesitylenesulfonic acid, naphthalenesulfonic acid and the like can be referred to. As the salts formed at the site of an acid group, for example, salts of alkali metals such as sodium, potassium and the like; salts of alkaline earth metals such as calcium, magnesium and the like; ammonium salts; and salts of nitrogen-containing organic bases such as trimethylamine, triethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl-β-phenethylamine, 1-ephenamine, and N,N′-dibenzylethylene-diamine and the like can be referred to. Of the salts mentioned above, preferred salts of the compound of general formula [1] are pharmacologically acceptable ones.

Among the compounds of the present invention, preferred are the compounds in which A represents a group of the following general formula:

wherein R^(aaa) represents hydrogen atom, an unprotected or protected carboxyl group, an unprotected or protected hydroxyl group or an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl, aralkyl, alkoxy, acyl, alkoxycarbonyl, amino or heterocyclic group; and Y^(aaa) represents oxygen atom, sulfur atom, carbonyl group, vinylene group, sulfinyl group or sulfonyl group; a group of the following general formula:

wherein R^(bbb) represents an unprotected or protected carboxyl group, an unprotected or protected hydroxyl group, substituted alkyl group or an unsubstituted or substituted alkenyl, cycloalkyl, aryl, aralkyl, alkoxy, acyl, alkoxycarbonyl, amino or heterocyclic group; a group of the following general formula:

wherein R^(ccc) and R^(ddd), same or different, each represents hydrogen atom, an unprotected or protected carboxyl group or an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl, alkoxy, acyl, alkoxycarbonyl, amino or heterocyclic group; or a group of the following general formula:

wherein R^(eee) and R^(fff), same or different, each represents an unprotected or protected carboxyl group, an unprotected or protected hydroxyl group or an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl, alkoxy, acyl, alkoxycarbonyl, amino or heterocyclic group; R² represents hydrogen atom or an unsubstituted or substituted alkyl, alkenyl, acyl, aryl, aralkyl, alkylsulfonyl, arylsulfonyl or heterocyclic group; R³ and R⁴, same or different, each represents hydrogen atom, an unprotected or protected carboxyl group or an unsubstituted or substituted alkyl, acyl, alkoxycarbonyl, carbamoyl group or a group of the following general formula:

—(CH₂)_(m)—CO—(D)_(p)—R⁷

wherein D represents amino acid residue; R⁷ represents hydroxyl group or amino group; p represents 1, 2 or 3; and m represents 0, 1, 2 or 3, or R³ and R⁴, taken conjointly, represent an oxo group; R⁵ and R⁶, same or different, each represents hydrogen atom, halogen atom, cyano group, an unprotected or protected carboxyl group, an unprotected or protected hydroxyl group, or an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, acyl, alkoxycarbonyl, aryl, amino, alkylamino, acylamino, carbamoyl or heterocyclic group, or R⁵ and R⁶, taken conjointly with the terminal carbon atom to which R⁵ and R⁶ are combined, represent an alkenyl group; and n represents 0, 1 or 2.

Also, preferred are the compounds in which A represents a group of the following general formula:

wherein R^(1ha) represents a group of the following general formula:

R^(11a)—Y^(2a)—

wherein R^(11a) represents an unsubstituted or substituted alkyl, alkenyl, aryl, alkoxy or heterocyclic group; and Y^(2a) represents methylene group, carbonyl group or sulfonyl group; or a group represented by the following general formula:

R¹²—(E¹)_(j)—

wherein E¹ represents amino acid residue; R¹² represents hydrogen atom or a protecting group for amino group; and j represents 2 or 3; R² represents hydrogen atom or an unsubstituted or substituted alkyl, alkenyl, aryl, aralkyl or heterocyclic group; R⁶ represents a group of the following general formula:

wherein R^(13aa) represents an unprotected or protected hydroxyl, amino, alkylamino, acylamino, alkoxycarbonylamino, arylsulfonylamino or alkylsulfonylamino group or an unsubstituted or substituted alkyl or alkoxy group; and k represents 1, 2 or 3; or a group of the following general formula:

R^(14a)—(E²)_(j)—

wherein E² represents amino acid residue; R^(14a) represents hydroxyl group or amino group; and j represents 1, 2 or 3.

Also, preferred are the compounds in which A represents a group of the following general formula:

wherein R^(1hb) represents a group of the following general formula:

R^(15a)—Y^(3a)—

wherein R^(15a) represents an unsubstituted or substituted alkyl, alkenyl, aryl or heterocyclic group; and Y^(3a) represents carbonyl group or a group of the following general formula:

R^(16a)—(E^(3a))_(s0)—

wherein E^(3a) represents amino acid residue; R^(16a) represents hydrogen atom or a protecting group for amino group; and s0 represents 2 or 3; R² represents hydrogen atom or an unsubstituted or substituted acyl group; R³ represents hydrogen atom; R⁴ represents carbamoyl group or a group of the following general formula:

—CO—(E^(4a))_(t0)—R^(18a)

wherein E^(4a) represents amino acid residue; R^(18a) represents hydroxyl group or amino group; and t0 represents 1, 2 or 3; R⁵ and R⁶, same or different, each represents hydrogen atom, an unsubstituted or substituted alkyl group; and n represents 0.

Among the compounds of the present invention, further preferred are the compounds in which A represents a group of the following general formula:

wherein R^(aa) represents an unsubstituted or substituted alkyl, alkenyl, aryl or heterocyclic group; and Y^(aa) represents oxygen atom or vinylene group; a group of the following general formula:

wherein R^(bb) represents an unsubstituted or substituted alkyl group or an unsubstituted or substituted alkenyl, aryl or heterocyclic group; a group of the following general formula:

wherein R^(cc) and R^(dd), same or different, each represents hydrogen atom or an unsubstituted or substituted alkyl, alkenyl, aryl or heterocyclic group; or a group of the following general formula:

wherein R^(ee) and R^(ff), same or different, each represents an unprotected or protected hydroxyl group or an unsubstituted or substituted aryl group; R² represents hydrogen atom, formyl group, alkanoyl group, aralkylcarbonyl group or an unsubstituted or substituted alkyl, alkenyl, aroyl, heterocycle-carbonyl, aryl, aralkyl or heterocyclic group; R³ and R⁴, same or different, each represents hydrogen atom, an unsubstituted or substituted alkoxycarbonyl, carbamoyl group or a group of the following general formula:

—(CH₂)_(m)—CO—(D)_(p)—R⁷

wherein D represents amino acid residue; R⁷ represents hydroxyl group or amino group; p represents 1, 2 or 3; and m represents 0, 1, 2 or 3, or R³ and R⁴, taken conjointly, represent an oxo group; R⁵ and R⁶, same or different, each represents hydrogen atom or an unsubstituted or substituted alkyl group; and n represents 0 or 2.

Also, further preferred are the compounds in which A represents a group of the following general formula:

wherein R^(1ha) represents a group of the following general formula:

R^(11a)—Y^(2a)—

wherein R^(11a) represents an unsubstituted or substituted alkyl, alkenyl, aryl or heterocyclic group; and Y^(2a) represents methylene group, carbonyl group or sulfonyl group; R² represents hydrogen atom or an unsubstituted or substituted alkyl or aralkyl group; R⁶ represents a group of the following general formula:

wherein R^(13a) represents an unprotected or protected hydroxyl, amino, alkylamino, acylamino, alkoxycarbonylamino, arylsulfonylamino or alkylsulfonylamino group or an unsubstituted or substituted alkoxy group; and k₀ represents 1; and n represents 0.

As representative examples of the compound of the present invention, the compounds of the following Tables 1 to 51 can be referred to.

TABLE 1

No. n R¹—Y— R² R³ R⁴ R⁵ R⁶  1 0 4-CH₃CH(CH₃)C₆H₄O— H COOH H H H  2 0 4-CH₃CH(CH₃)C₆H₄O— CH₃ COOH H H H  3 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₃ COOH H H H  4 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂CH₃ COOH H H H  5 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂CH₂CH₃ COOH H H H  6 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂CH₂CH₂CH₃ COOH H H H  7 0 4-CH₃CH(CH₃)C₆H₄O— CH(CH₃)CH₃ COOH H H H  8 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH(CH₃)CH₃ COOH H H H  9 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂CH(CH₃)CH₃ COOH H H H 10 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂CH₂CH(CH₃)CH₃ COOH H H H 11 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH(CH₃)C₂H₅ COOH H H H 12 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂CH(CH₃)C₂H₅ COOH H H H 13 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂CH(C₂H₅)C₂H₅ COOH H H H 14 0 4-CH₃CH(CH₃)C₆H₄O— CH₂F COOH H H H 15 0 4-CH₃CH(CH₃)C₆H₄O— CH₂OH COOH H H H

TABLE 2 No. n R¹—Y— R² R³ R⁴ R⁵ R⁶ 16 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂OH COOH H H H 17 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂CH₂OH COOH H H H 18 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂CH₂CH₂OH COOH H H H 19 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂CH₂CH₂CH₂OH COOH H H H 20 0 4-CH₃CH(CH₃)C₆H₄O— CH(OH)CH₂OH COOH H H H 21 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH(OH)CH₂OH COOH H H H 22 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH(OH)CH₂CH₂OH COOH H H H 23 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂CH(OH)CH₂CH₂OH COOH H H H 24 0 4-CH₃CH(CH₃)C₆H₄O— CH₂OC(O)NH₂ COOH H H H 25 0 4-CH₃CH(CH₃)C₆H₄O— CH₂OC(O)CH₃ COOH H H H 26 0 4-CH₃CH(CH₃)C₆H₄O— CH₂COOH COOH H H H 27 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOH COOH H H H 28 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂CH₂COOH COOH H H H 29 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂CH₂CH₂COOH COOH H H H 30 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂CH₂CH₂CH₂COOH COOH H H H 31 0 4-CH₃CH(CH₃)C₆H₄O— CH₂COOCH₃ COOH H H H 32 0 4-CH₃CH(CH₃)C₆H₄O— CH₂COOC₂H₅ COOH H H H 33 0 4-CH₃CH(CH₃)C₆H₄O— CH₂COO-n-C₃H₇ COOH H H H 34 0 4-CH₃CH(CH₃)C₆H₄O— CH₂COO-i-C₃H₇ COOH H H H 35 0 4-CH₃CH(CH₃)C₆H₄O— CH₂COOC₆H₅ COOH H H H

TABLE 3 No. n R¹—Y— R² R³ R⁴ R⁵ R⁶ 36 0 4-CH₃CH(CH₃)C₆H₄O— CH₂COOCH₂C₆H₅ COOH H H H 37 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CONH₂ COOH H R H 38 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CONHOH COOH H H H 39 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CONHCH₃ COOH H H H 40 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CONHC₂H₅ COOH H H H 41 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CONH-n-C₃H₇ COOH H H H 42 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CONH-i-C₃H₇ COOH H H H 43 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CON(CH₃)₂ COOH H H H 44 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CON(n-C₃H₇)₂ COOH H H H 45 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CON(C₂H₅)₃ COOH H H H 46 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CONHC₆H₅ COOH H H H 47 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₃ COOH H H H 48 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ COOH H H H 49 0 4-CH₃CH(CH₃)C₆H₄O— CH(CH₃)COOH COOH H H H 50 0 4-CH₃CH(CH₃)C₆H₄O— CH(CH₂OH)COOH COOH H H H 51 0 4-CH₃CH(CH₃)C₆H₄O— CH(CH₂COOH)COOH COOH H H H 52 0 4-CH₃CH(CH₃)C₆H₄O— CH(CH₂CONH₂)COOH COOH H H H 53 0 4-CH₃CH(CH₃)C₆H₄O— CH(CH₂CH₂COOH)COOH COOH H H H 54 0 4-CH₃CH(CH₃)C₆H₄O— CH(CH₂CH₂CONH₂)COOH COOH H H H 55 0 4-CH₃CH(CH₃)C₆H₄O— CH(4-Imidazolylmethyl)COOH COOH H H H

TABLE 4 No. n R¹—Y— R² R³ R⁴ R⁵ R⁶ 56 0 4-CH₃CH(CH₃)C₆H₄O— CH(CH(C₂H₅)CH₃)COOH COOH H H H 57 0 4-CH₃CH(CH₃)C₆H₄O— CH(CH₂CH(CH₃)CH₃)COOH COOH H H H 58 0 4-CH₃CH(CH₃)C₆H₄O— CH(CH₂CH₂SCH₃)COOH COOH H H H 59 0 4-CH₃CH(CH₃)C₆H₄O— CH(CH(OH)CH₃)COOH COOH H H H 60 0 4-CH₃CH(CH₃)C₆H₄O— CH(CH₂-(4-HO)C₆H₅)COOH COOH H H H 61 0 4-CH₃CH(CH₃)C₆H₄O— CH(CH₂C₆H₅)COOH COOH H H H 62 0 4-CH₃CH(CH₃)C₆H₄O— CH(3-Indolylmethyl)COOH COOH H H H 63 0 4-CH₃CH(CH₃)C₆H₄O— CH(i-C₃H₇) COOH COOH H H H 64 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CN COOH H H H 65 0 4-CH₃CH(CH₃)C₆H₄O— CH₂NO₂ COOH H H H 66 0 4-CH₃CH(CH₃)C₆H₄O— CH₂COCH₃ COOH H H H 67 0 4-CH₃CH(CH₃)C₆H₄O— CH₂C(NOH)CH₃ COOH H H H 68 0 4-CH₃CH(CH₃)C₆H₄O— CH₂SO₃H COOH H H H 69 0 4-CH₃CH(CH₃)C₆H₄O— CH₂S(O)₂CH₃ COOH H H H 70 0 4-CH₃CH(CH₃)C₆H₄O— CH₂S(O)CH₃ COOH H H H 71 0 4-CH₃CH(CH₃)C₆H₄O— CH₂SO₂NH₂ COOH H H H 72 0 4-CH₃CH(CH₃)C₆H₄O— CH₂SO₃CH₃ COOH H H H 73 0 4-CH₃CH(CH₃)C₆H₄O— CH₂OCH₃ COOH H H H 74 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂OCH₃ COOH H H H 75 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂CH₂OCH₃ COOH H H H

TABLE 5 No. n R¹—Y— R² R³ R⁴ R⁵ R⁶ 76 0 4-CH₃CH(CH₃)C₆H₄O— CH₂SCH₃ COOH H H H 77 0 4-CH₃CH(CH₃)C₆H₄O— CHCH₂ COOH H H H 78 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CHCH₂ COOH H H H 79 0 4-CH₃CH(CH₃)C₆H₄O— CHCHCH₃ COOH H H H 80 0 4-CH₃CH(CH₃)C₆H₄O— Cyclopropyl COOH H H H 81 0 4-CH₃CH(CH₃)C₆H₄O— Cyclobutyl COOH H H H 82 0 4-CH₃CH(CH₃)C₆H₄O— Cyclopentyl COOH H H H 83 0 4-CH₃CH(CH₃)C₆H₄O— Cyclohexyl COOH H H H 84 0 4-CH₃CH(CH₃)C₆H₄O— CH₂C₆H₅ COOH H H H 85 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂C₆H₅ COOH H H H 86 0 4-CH₃CH(CH₃)C₆H₄O— CH₂C₆H₁₁ COOH H H H 87 0 4-CH₃CH(CH₃)C₆H₄O— CH(CH₃)C₆H₅ COOH H H H 88 0 4-CH₃CH(CH₃)C₆H₄O— 2-Thienylmethyl COOH H H H 89 0 4-CH₃CH(CH₃)C₆H₄O— 2-Furfuryl COOH H H H 90 0 4-CH₃CH(CH₃)C₆H₄O— 2-Pyranylmethyl COOH H H H 91 0 4-CH₃CH(CH₃)C₆H₄O— 1-Isobenzofurylmethyl COOH H H H 92 0 4-CH₃CH(CH₃)C₆H₄O— 2-Pyrrolylmethyl COOH H H H 93 0 4-CH₃CH(CH₃)C₆H₄O— 1-Imidazolylmethyl COOH H H H 94 0 4-CH₃CH(CH₃)C₆H₄O— 1-Pyrazolylmethyl COOH H H H 95 0 4-CH₃CH(CH₃)C₆H₄O— 3-Isothiazolylmethyl COOH H H H

TABLE 6 No. n R¹—Y— R² R³ R⁴ R⁵ R⁶ 96 0 4-CH₃CH(CH₃)C₆H₄O— 3-Isoxazolylmethyl COOH H H H 97 0 4-CH₃CH(CH₃)C₆H₄O— 2-Pyridylmethyl COOH H H H 98 0 4-CH₃CH(CH₃)C₆H₄O— 2-Pyrazinylmethyl COOH H H H 99 0 4-CH₃CH(CH₃)C₆H₄O— 2-Pyrimidinylmethyl COOH H H H 100 0 4-CH₃CH(CH₃)C₆H₄O— 3-Pyridazinylmethyl COOH H H H 101 0 4-CH₃CH(CH₃)C₆H₄O— 1-Isoindolylmethyl COOH H H H 102 0 4-CH₃CH(CH₃)C₆H₄O— 2-Indolylmethyl COOH H H H 103 0 4-CH₃CH(CH₃)C₆H₄O— 3-(1H—Indazolyl)methyl COOH H H H 104 0 4-CH₃CH(CH₃)C₆H₄O— 2-Purinylmethyl COOH H H H 105 0 4-CH₃CH(CH₃)C₆H₄O— 1-Isoquinolylmethyl COOH H H H 106 0 4-CH₃CH(CH₃)C₆H₄O— 2-Quinolylmethyl COOH H H H 107 0 4-CH₃CH(CH₃)C₆H₄O— 1-Phthalazinylmethyl COOH H H H 108 0 4-CH₃CH(CH₃)C₆H₄O— 2-Naphthylidinylmethyl COOH H H H 109 0 4-CH₃CH(CH₃)C₆H₄O— 2-Quinoxalinylmethyl COOH H H H 110 0 4-CH₃CH(CH₃)C₆H₄O— 2-Quinazolinylmethyl COOH H H H 111 0 4-CH₃CH(CH₃)C₆H₄O— 3-Cinnolinylmethyl COOH H H H 112 0 4-CH₃CH(CH₃)C₆H₄O— 2-Oxazolylmethyl COOH H H H 113 0 4-CH₃CH(CH₃)C₆H₄O— 2-Thiazolylmethyl COOH H H H 114 0 4-CH₃CH(CH₃)C₆H₄O— 2-Benzo[b]furylmethyl COOH H H H 115 0 4-CH₃CH(CH₃)C₆H₄O— 2-Benzo[b]thienylmethyl COOH H H H

TABLE 7 No. n R¹—Y— R² R³ R⁴ R⁵ R⁶ 116 0 4-CH₃CH(CH₃)C₆H₄O— 3-(l,2,4-Triazinyl)methyl COOH H H H 117 0 4-CH₃CH(CH₃)C₆H₄O— 2-Benz[d]imidazolylmethyl COOH H H H 118 0 4-CH₃CH(CH₃)C₆H₄O— 2-Benz[d]oxazolylmethyl COOH H H H 119 0 4-CH₃CH(CH₃)C₆H₄O— Phenyl COOH H H H 120 0 4-CH₃CH(CH₃)C₆H₄O— 2-Thiazolyl COOH H H H 121 0 4-CH₃CH(CH₃)C₆H₄O— 4-Imidazolyl COOH H H H 122 0 4-CH₃CH(CH₃)C₆H₄O— 3-Pyrazolyl COOH H H H 123 0 4-CH₃CH(CH₃)C₆H₄O— 3-Isoxazolyl COOH H H H 124 0 4-CH₃CH(CH₃)C₆H₄O— 5-Isothiazolyl COOH H H H 125 0 4-CH₃CH(CH₃)C₆H₄O— 2-Pyrimidinyl COOH H H H 126 0 4-CH₃CH(CH₃)C₆H₄O— 3-(1,2,4-Triazolyl) COOH H H H 127 0 4-CH₃CH(CH₃)C₆H₄O— 2-Pyridyl COOH H H H 128 0 4-CH₃CH(CH₃)C₆H₄O— 2-Benzoxazolyl COOH H H H 129 0 4-CH₃CH(CH₃)C₆H₄O— 3-Benzothienyl COOH H H H 130 0 4-CH₃CH(CH₃)C₆H₄O— 2-Benzofuryl COOH H H H 131 0 4-CH₃CH(CH₃)C₆H₄O— 5-Indolyl COOH H H H 132 0 4-CH₃CH(CH₃)C₆H₄O— 2-Pyrazinyl COOH H H H 133 0 4-CH₃CH(CH₃)C₆H₄O— 3-Quinolinyl COOH H H H 134 0 4-CH₃CH(CH₃)C₆H₄O— 5-Tetrazolyl COOH H H H 135 0 4-CH₃CH(CH₃)C₆H₄O— Methylsulfonyl COOH H H H

TABLE 8 No. n R¹—Y— R² R³ R⁴ R⁵ R⁶ 136 0 4-CH₃CH(CH₃)C₆H₄O— Benzenesulfonyl COOH H H H 137 0 4-CH₃CH(CH₃)C₆H₄O— COCH₃ COOH H H H 138 0 4-CH₃CH(CH₃)C₆H₄O— COCH₂CH₃ COOH H H H 139 0 4-CH₃CH(CH₃)C₆H₄O— COCH₂CH₂CH₃ COOH H H H 140 0 4-CH₃CH(CH₃)C₆H₄O— COCH₂CH₂CH₂CH₃ COOH H H H 141 0 4-CH₃CH(CH₃)C₆H₄O— COCH₂CH₂CH₂CH₂CH₃ COOH H H H 142 0 4-CH₃CH(CH₃)C₆H₄O— COCH(CH₃)CH₃ COOH H H H 143 0 4-CH₃CH(CH₃)C₆H₄O— COCH₂CH(CH₃)CH₃ COOH H H H 144 0 4-CH₃CH(CH₃)C₆H₄O— COCH₂C₆H₅ COOH H H H 145 0 4-CH₃CH(CH₃)C₆H₄O— 2-Thienylmethylcarbonyl COOH H H H 146 0 4-CH₃CH(CH₃)C₆H₄O— 2-Furfurylcarbonyl COOH H H H 147 0 4-CH₃CH(CH₃)C₆H₄O— 2-Pyridylmethylcarbonyl COOH H H H 148 0 4-CH₃CH(CH₃)C₆H₄O— 2-Quinolylmethylcarbonyl COOH H H H 149 0 4-CH₃CH(CH₃)C₆H₄O— 2-Benzothienylmethylcarbonyl COOH H H H 150 0 4-CH₃CH(CH₃)C₆H₄O— 2-Naphthylidinylcarboxyl COOH H H H 151 0 4-CH₃CH(CH₃)C₆H₄O— 2-thiazolylmethylcarbonyl COOH H H H 152 0 4-CH₃CH(CH₃)C₆H₄O— 2-Pyrimidinylmethylcarbonyl COOH H H H 153 0 4-CH₃CH(CH₃)C₆H₄O— 2-Benzoxazolylmethylcarbonyl COOH H H H 154 0 4-CH₃CH(CH₃)C₆H₄O— 2-Indolylmethylcarbonyl COOH H H H 155 0 4-CH₃CH(CH₃)C₆H₄O— 2-Thiazolylcarbonyl COOH H H H

TABLE 9 No. n R¹—Y— R² R³ R⁴ R⁵ R⁶ 156 0 4-CH₃CH(CH₃)C₆H₄O— 2-Pyrimidinylcarbonyl COOH H H H 157 0 4-CH₃CH(CH₃)C₆H₄O— 2-Indolylcarbonyl COOH H H H 158 0 4-CH₃CH(CH₃)C₆H₄O— 2-Benzothienylcarbonyl COOH H H H 159 0 4-CH₃CH(CH₃)C₆H₄O— 5-Quinolylcarbonyl COOH H H H 160 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CONHCH₂C₆H₅ COOH H H H 161 0 4-FC₆H₄O— COC₆H₅ COOH H H H 162 0 2-CH₃C₆H₄O— COC₆H₅ COOH H H H 163 0 3-CH₃C₆H₄O— COC₆H₅ COOH H H H 164 0 4-CH₃C₆H₄O— COC₆H₅ COOH H H H 165 0 2,4-(CH₃)₂C₆H₃O— COC₆H₅ COOH H H H 166 0 3,4-(CH₃)₂C₆H₃O— COC₆H₅ COOH H H H 167 0 2,3-(CH₃)₂C₆H₃O— COC₆H₅ COOH H H H 168 0 3,5-(CH₃)₂C₆H₃O— COC₆H₅ COOH H H H 169 0 3,6-(CH₃)₂C₆H₃O— COC₆H₅ COOH H H H 170 0 2,6-(CH₃)₂C₆H₃O— COC₆H₅ COOH H H H 171 0 2,5-(CH₃)₂C₆H₃O— COC₆H₅ COOH H H H 172 0 2,4,6-(CH₃)₃C₆H₂O— COC₆H₅ COOH H H H 173 0 2,3,5-(CH₃)₃C₆H₂O— COC₆H₅ COOH H H H 174 0 2,4,5-(CH₃)₃C₆H₂O— COC₆H₅ COOH H H H 175 0 2,5,6-(CH₃)₃C₆H₂O— COC₆H₅ COOH H H H

TABLE 10 No. n R¹—Y— R² R³ R⁴ R⁵ R⁶ 176 0 4-HOC₆H₄O— COC₆H₅ COOH H H H 177 0 4-CH₃OC₆H₄O— COC₆H₅ COOH H H H 178 0 4-C₂H₅OC₆H₄O— COC₆H₅ COOH H H H 179 0 4- COC₆H₅ COOH H H H CH₃CH(CH₃)OC₆H₄O— 180 0 4-C₆H₅OC₆H₄O— COC₆H₅ COOH H H H 181 0 4-C₆H₅CH₂OC₆H₄O— COC₆H₅ COOH H H H 182 0 4-HO₂CC₆H₄O— COC₆H₅ COOH H H H 183 0 4-CH₃COC₆H₄O— COC₆H₅ COOH H H H 184 0 4-CH₃OC(O)C₆H₄O— COC₆H₅ COOH H H H 185 0 4-H₂NC(O)C₆H₄O— COC₆H₅ COOH H H H 186 0 4-HONHC(O)C₆H₄O— COC₆H₅ COOH H H H 187 0 4-H₃CNHC(O)C₆H₄O— COC₆H₅ COOH H H H 188 0 4-(H₃C)₂NC(O)C₆H₄O— COC₆H₅ COOH H H H 189 0 4-O₂NC₆H₄O— COC₆H₅ COOH H H H 190 0 4-H₂NC₆H₄O— COC₆H₅ COOH H H H 191 0 4-H₃CNHC₆H₄O— COC₆H₅ COOH H H H 192 0 4-(H₃C)₂NC₆H₄O— COC₆H₅ COOH H H H 193 0 4-OHCC₆H₄O— COC₆H₅ COOH H H H 194 0 4-CH(NOH)C₆H₄O— COC₆H₅ COOH H H H 195 0 4-OHCNHC₆H₄O— COC₆H₅ COOH H H H

TABLE 11 No. n R¹—Y— R² R³ R⁴ R⁵ R⁶ 196 0 4-CH₃C(O)NHC₆H₄O— COC₆H₅ COOH H H H 197 0 4- COC₆H₅ COOH H H H CH₃OC(O)NHC₆H₄O— 198 0 4-H₂NC(O)OC₆H₄O— COC₆H₅ COOH H H H 199 0 4-HSC₆H₄O— COC₆H₅ COOH H H H 200 0 4-H₃CSC₆H₄O— COC₆H₅ COOH H H H 201 0 4-H₃CS(O)C₆H₄O— COC₆H₅ COOH H H H 202 0 4-H₃CS(O)₂C₆H₄O— COC₆H₅ COOH H H H 203 0 3,4-(OCH₂O)C₆H₃O— COC₆H₅ COOH H H H 204 0 3,4- COC₆H₅ COOH H H H (CH₂CH₂CH₂)C₆H₃O— 205 0 4-HO₃SC₆H₄O— COC₆H₅ COOH H H H 206 0 4-NCC₆H₄O— COC₆H₅ COOH H H H 207 0 4-H₂NC(NH)C₆H₄O— COC₆H₅ COOH H H H 208 0 3-Isoxazoloxy COC₆H₅ COOH H H H 209 0 2-Imidazoloxy COC₆H₅ COOH H H H 210 0 2-Benzimidazoloxy COC₆H₅ COOH H H H 211 0 2-Thiazoloxy COC₆H₅ COOH H H H 212 0 5-Benzo[b]thienyloxy COC₆H₅ COOH H H H 213 0 2-Thiazolylamino COC₆H₅ COOH H H H 214 0 4-Imidazolylamino COC₆H₅ COOH H H H 215 0 3-Pyrazolylamino COC₆H₅ COOH H H H

TABLE 12 No. n R¹—Y— R² R³ R⁴ R⁵ R⁶ 216 0 3-Isoxazolylamino COC₆H₅ COOH H H H 217 0 5-Isothiazolylamino COC₆H₅ COOH H H H 218 0 2-Pyrimidinylamino COC₆H₅ COOH H H H 219 0 3-(1,2,4-Triazolyl)amino COC₆H₅ COOH H H H 220 0 2-Pyridylamino COC₆H₅ COOH H H H 221 0 2-Benzoxazolylamino COC₆H₅ COOH H H H 222 0 3-Benzothienylamino COC₆H₅ COOH H H H 223 0 2-Benzofurylamino COC₆H₅ COOH H H H 224 0 5-Indolylamino COC₆H₅ COOH H H H 225 0 2-Pyrazinylamino COC₆H₅ COOH H H H 226 0 3-Quinolylamino COC₆H₅ COOH H H H 227 0 5-Tetrazolylamino COC₆H₅ COOH H H H 228 0 2-Imidazolylthioxy COC₆H₅ COOH H H H 229 0 2-Pyridylthioxy COC₆H₅ COOH H H H 230 0 2-Benzothiazolylthioxy COC₆H₅ COOH H H H 231 0 2-Benzothienylethenyl COC₆H₅ COOH H H H 232 0 2-Benzothienylmethyl COC₆H₅ COOH H H H 233 0 4-CH₃CH(CH₃)C₆H₄S(O)₂— COC₆H₅ COOH H H H 234 0 4-CH₃CH(CH₃)C₆H₄S— COC₆H₅ COOH H H H 235 0 4-CH₃CH(CH₃)C₆H₄NH— COC₆H₅ COOH H H H

TABLE 13 No. n R¹—Y— R² R³ R⁴ R⁵ R⁶ 236 0 4-CH₃CH(CH₃)C₆H₄CO— COC₆H₅ COOH H H H 237 0 4-CH₃CH(CH₃)C₆H₄CH(OH)— COC₆H₅ COOH H H H 238 0 4-CH₃CH(CH₃)C₆H₄CH₂OC(O)— COC₆H₅ COOH H H H 239 0 4-CH₃CH(CH₃)C₆H₄NHC(O)— COC₆H₅ COOH H H H 240 0 4-CH₃CH(CH₃)C₆H₄OC(O)NH— COC₆H₅ COOH H H H 241 0 4-CH₃CH(CH₃)C₆H₄CH₂OC(O)NH— COC₆H₅ COOH H H H 242 0 4-CH₃CH(CH₃)C₆H₄C(O)NH— COC₆H₅ COOH H H H 243 0 4-CH₃CH(CH₃)C₆H₄CH₂C(O)NH— COC₆H₅ COOH H H H 244 0 4-CH₃CH(CH₃)C₆H₄CH₂CO— COC₆H₅ COOH H H H 245 0 4-CH₃CH(CH₃)C₆H₄CH₂OCH₂— COC₆H₅ COOH H H H 246 0 4-CH₃CH(CH₃)C₆H₄C(NOH)— COC₆H₅ COOH H H H 247 0 4-CH₃CH(CH₃)C₆H₄CHCH— COC₆H₅ COOH H H H 248 0 4-CH₃CH(CH₃)C₆H₄CH₂— COC₆H₅ COOH H H H 249 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ CH₂OH H H H 250 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ CHFCOOH H H H 251 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ COCOOH H H H 252 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ C(NOH)COOH H H H 253 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ CH(CH₂OH)COOH H H H 254 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ CH(NH₂)COOH H H H 255 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ CH(NHCHO)COOH H H H

TABLE 14 No. n R¹—Y— R² R³ R⁴ R⁵ R⁶ 256 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ CF₂COOH H H H 257 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ CH(OH)COOH H H H 258 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ CH(OCH₃)COOH H H H 259 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ CH(CH₃)COOH H H H 260 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ CH(C₆H₅)COOH H H H 261 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ C(CH₃)₂COOH H H H 262 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ C(C₂H₄)COOH H H H 263 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ C(C₃H₆)COOH H H H 264 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ C(C₄H₆)COOH H H H 265 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ C(C₅H₁₀)COOH H H H 266 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ CONHOH H H H 267 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ CON(CH₃)₂ H H H 268 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ CONHC₆H₅ H H H 269 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ COC₆H₅ H H H 270 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ COCH₃ H H H 271 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ CH₂COOH H H H 272 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ CH₂COOCH₃ H H H 273 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ CH₂CH₂COOH H H H 274 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ CH₂CH(OH)COOH H H H 275 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ CH(OH)CH₂COOH H H H

TABLE 15 No. n R¹—Y— R² R³ R⁴ R⁵ R⁶ 276 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ CH₂CF₂COOH H H H 277 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ CH₂CHFCOOH H H H 278 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ CH₂CH₂OH H H H 279 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ CH₂CH₂OCH₃ H H H 280 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ CH₂CH₂OC₆H₅ H H H 281 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ CH₂CH₂OCH₂C₆H₅ H H H 282 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ CH₂CH₂F H H H 283 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ CH₂F H H H 284 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ CH₂NH₂ H H H 285 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ CH₂CH₂NH₂ H H H 286 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ CH₂CH₂NHCHO H H H 287 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ CH₂CH₂NHCOOCH₃ H H H 288 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ CH₂CH₂N(CH₃)₂ H H H 289 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ CH₂CH₂NHCH₃ H H H 290 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ CH₂SH H H H 291 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ CH₂CH₂SH H H H 292 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ CH₂SCH₃ H H H 293 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ CH₂S(O)₂CH₃ H H H 294 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ CH₂S(O)CH₃ H H H 295 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ CONHCH(CH₂COOH)COOH H H H

TABLE 16 No. n R¹-Y- R² R³ R⁴ R⁵ R⁶ 296 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ CONHCH(CH₃)COOH H H H 297 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ CONHCH(CHCH₂(CH₃)COOH H H H 298 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ CONHCH(CH₂OH)COOH H H H 299 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ CONHCH(CH₂CH₂SCH₃)COOH H H H 300 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ CONHCH((CH₂)₄NH₂)COOH H H H 301 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ CONHCH(C₆H₅)COOH H H H 302 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ CONHCH(CH₂CONH₂)COOH H H H 303 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ CONH₂ H H H 304 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ CH₂CONH₂ H H H 305 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ CONHCH₂ H H H 306 0 CH₃C(O)S— COC₆H₅ COOH H H H 307 0 OHC— COC₆H₅ COOH H H H 308 0 O₂NCHCH— COC₆H₅ COOH H H H 309 0 CH₂CHCHCH— COC₆H₅ COOH H H H 310 0 CH₃OCHCH— COC₆H₅ COOH H H H 311 0 CH₃COCHCH— COC₆H₅ COOH H H H 312 0 CH₂CH— COC₆H₅ COOH H H H 313 0 ClCH₂CH₂— COC₆H₅ COOH H H H 314 0 NCCH₂— COC₆H₅ COOH H H H 315 0 O₂NCH₂— COC₆H₅ COOH H H H

TABLE 17 No. n R¹—Y— R² R³ R⁴ R⁵ R⁶ 316 0 CH₃OC(O)CH₂— COC₆H₅ COOH H H H 317 0 HOC(O)CH₂— COC₆H₅ COOH H H H 318 0 4-CH₃CH(CH₃)C₆H₄O— COCH₃ COOH H CH₃ CH₃ 319 0 4-CH₃CH(CH₃)C₆H₄O— COCH₂CH₃ COOH H CH₃ CH₃ 320 0 4-CH₃CH(CH₃)C₆H₄O— COCH₂CH₂CH₃ COOH H CH₃ CH₃ 321 0 4-CH₃CH(CH₃)C₆H₄O— COCH₂CH₂CH₂CH₃ COOH H CH₃ CH₃ 322 0 4-CH₃CH(CH₃)C₆H₄O— COCH₂CH₂CH₂CH₂CH₃ COOH H CH₃ CH₃ 323 0 4-CH₃CH(CH₃)C₆H₄O— COCH(CH₃)CH₃ COOH H CH₃ CH₃ 324 0 4-CH₃CH(CH₃)C₆H₄O— COCH₂CH(CH₃)CH₃ COOH H CH₃ CH₃ 325 0 4-CH₃CH(CH₃)C₆H₄O— COCH₂C₆H₅ COOH H CH₃ CH₃ 326 0 4-CH₃CH(CH₃)C₆H₄O— 2-Thienylmethylcarbonyl COOH H CH₃ CH₃ 327 0 4-CH₃CH(CH₃)C₆H₄O— 2-Furfurylcarbonyl COOH H CH₃ CH₃ 328 0 4-CH₃CH(CH₃)C₆H₄O— 2-Pyridylmethylcarbonyl COOH H CH₃ CH₃ 329 0 4-CH₃CH(CH₃)C₆H₄O— 2-Quinolylmethylcarbonyl COOH H CH₃ CH₃ 330 0 4-CH₃CH(CH₃)C₆H₄O— 2-Benzothienylmethylcarbonyl COOH H CH₃ CH₃ 331 0 4-CH₃CH(CH₃)C₆H₄O— 2-Naphthylidinylcarbonyl COOH H CH₃ CH₃ 332 0 4-CH₃CH(CH₃)C₆H₄O— 2-Thiazolylmethylcarbonyl COOH H CH₃ CH₃ 333 0 4-CH₃CH(CH₃)C₆H₄O— 2-Pyrimidinylmethylcarbonyl COOH H CH₃ CH₃ 334 0 4-CH₃CH(CH₃)C₆H₄O— 2-Benzoxazolylmethylcarbonyl COOH H CH₃ CH₃ 335 0 4-CH₃CH(CH₃)C₆H₄O— 2-Indolylmethylcarbonyl COOH H CH₃ CH₃

TABLE 18 No. n R¹—Y— R² R³ R⁴ R⁵ R⁶ 336 0 4-CH₃CH(CH₃)C₆H₄O— 2-Thiazolylcarbonyl COOH H CH₃ CH₃ 337 0 4-CH₃CH(CH₃)C₆H₄O— 2-Pyrimidinylcarbonyl COOH H CH₃ CH₃ 338 0 4-CH₃CH(CH₃)C₆H₄O— 2-Indolylcarbonyl COOH H CH₃ CH₃ 339 0 4-CH₃CH(CH₃)C₆H₄O— 2-Benzothienylcarbonyl COOH H CH₃ CH₃ 340 0 4-CH₃CH(CH₃)C₆H₄O— 5-Quinolylcarbonyl COOH H CH₃ CH₃ 341 0 HO— COC₆H₅ COOH H H H 342 0 O₂NO— COC₆H₅ COOH H H H 343 0 H₂NC(O)O— COC₆H₅ COOH H H H 344 0 HS— COC₆H₅ COOH H H H 345 0 HOS— COC₆H₅ COOH H H H 346 0 (HO₂)CH— COC₆H₅ COOH H H H 347 0 CH₃O— COC₆H₅ COOH H H H 348 0 CH₃S— COC₆H₅ COOH H H H 349 0 CH₃NH— COC₆H₅ COOH H H H 350 0 CH₃CO— COC₆H₅ COOH H H H 351 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ C(NOH)CH₃ H H H 352 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ CHO H H H 353 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ CH₂OC(O)NH₂ H H H 354 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ CH₂OC(O)CH₃ H H H 355 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ CH₂OC(O)C₆H₅ H H H

TABLE 19 No. n R¹—Y— R² R³ R⁴ R⁵ R⁶ 356 1 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ CH₂COOH H H H 357 2 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ CH₂COOH H H H 358 0 CH₃COCH₂— COC₆H₅ COOH H H H 359 0 H₂NCH₂ COC₆H₅ COOH H H H 360 0 HOCH₂— COC₆H₅ COOH H H H 361 0 HONH— COC₆H₅ COOH H H H 362 0 CH₃C(O)NCl— COC₆H₅ COOH H H H 363 0 O₂NNH— COC₆H₅ COOH H H H 364 0 CH₃ONH— COC₆H₅ COOH H H H 365 0 H₂NNH— COC₆H₅ COOH H H H 366 0 H₂N— COC₆H₅ COOH H H H 367 0 ClCO— COC₆H₅ COOH H H H 368 0 ClCHCH COC₆H₅ COOH H H H 369 0 ClS(O)₂— COC₆H₅ COOH H H H 370 0 HOS(O)₂— COC₆H₅ COOH H H H 371 0 NCS(O)₂— COC₆H₅ COOH H H H 372 0 CH₃OS(O)₂— COC₆H₅ COOH H H H 373 0 H₂NS(O)₂— COC₆H₅ COOH H H H 374 0 NCCO— COC₆H₅ COOH H H H 375 0 NCCHCH— COC₆H₅ COOH H H H

TABLE 20 No. n R¹—Y— R² R³ R⁴ R⁵ R⁶ 376 0 NCS— COC₆H₅ COOH H H H 377 0 OCN— COC₆H₅ COOH H H H 378 0 HOC(O)CO— COC₆H₅ COOH H H H 379 0 CH₃OC(O)NH— COC₆H₅ COOH H H H 380 0 HOC(O)CHCH— COC₆H₅ COOH H H H 381 0 HOC(O)CH(OH)— COC₆H₅ COOH H H H 382 0 HOO— COC₆H₅ COOH H H H 383 0 HOC(O)— COC₆H₅ COOH H H R 384 0 CH₃C(O)OCHCH COC₆H₅ COOH H H H 385 0 CH₃C(O)SCHCH COC₆H₅ COOH H H H 386 0 CH₃OC(O)— COC₆H₅ COOH H H H 387 0 CH₃OC(O)CHCH— COC₆H₅ COOH H H H 388 0 CH₃C(O)NHCHCH— COC₆H₅ COOH H H H 389 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ COOH H C₆H₅ C₆H₅ 390 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ COOH H C₆H₅ CH₃ 391 0 CH₃CHCH— COC₆H₅ COOH H H H 392 0 C₆H₅S(O)— COC₆H₅ COOH H H H 393 0 CH₃S(O)— COC₆H₅ COOH H H H 394 0 CH₃S(O)₂— COC₆H₅ COOH H H H 395 0 NCCH(OH)— COC₆H₅ COOH H H H

TABLE 21 No. n R¹—Y— R² R³ R⁴ R⁵ R⁶ 396 0 CH₃OC(O)CH(OH)— COC₆H₅ COOH H H H 397 0 CH₃COCH(OH)— COC₆H₅ COOH H H H 398 0 CH₃CH(OH)— COC₆H₅ COOH H H H 399 0 CH₂CHO— COC₆H₅ COOH H H H 400 0 CH₂CHS— COC₆H₅ COOH H H H 401 0 CH₂CHNH— COC₆H₅ COOH H H H 402 0 CH₂CHCO— COC₆H₅ COOH H H H 403 0 CH₂CHCH₂— COC₆H₅ COOH H H H 404 0 CH₂CHS(O)— COC₆H₅ COOH H H H 405 0 CH₂CHS(O)₂— COC₆H₅ COOH H H H 406 0 2-Thiazolylsulfonyl COC₆H₅ COOH H H H 407 0 CH₂CHCH(OH)— COC₆H₅ COOH H H H 408 0 C₆H₁₁O— COC₆H₅ COOH H H H 409 0 C₆H₁₁S— COC₆H₅ COOH H H H 410 0 C₆H₁₁NH— COC₆H₅ COOH H H H 411 0 C₆H₁₁CHCH— COC₆H₅ COOH H H H 412 0 C₆H₁₁S(O)— COC₆H₅ COOH H H H 413 0 C₆H₁₁S(O)₂— COC₆H₅ COOH H H H 414 0 C₆H₁₁CH(OH)— COC₆H₅ COOH H H H 415 0 CH₃C(O)O— COC₆H₅ COOH H H H

TABLE 22 No. n R¹—Y— R² R³ R⁴ R⁵ R⁶ 416 0 C₆H₅CH₂C(O)O— COC₆H₅ COOH H H H 417 0 CH₃C(O)NH— COC₆H₅ COOH H H H 418 0 H₂NC(O)— COC₆H₅ COOH H H H 419 0 C₆H₅CH₂CH₂— COC₆H₅ COOH H H H 420 0 2-Pyridylethenyl COC₆H₅ COOH H H H 421 0 C₆H₅CHCH— COC₆H₅ COOH H H H 422 0 CH₃COCO— COC₆H₅ COOH H H H 423 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ COOH H H Cl 424 0 Cyclohexanecarbonyl COC₆H₅ COOH H H H 425 0 2-Thienylcarbonyl COC₆H₅ COOH H H H 426 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ COOH CH₃ CH₃ CH₃ 427 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ COOH CH₂COOH CH₃ CH₃ 428 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ COOH CN CH₃ CH₃ 429 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ COOH CONH₂ CH₃ CH₃ 430 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ COOH F CH₃ CH₃ 431 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ COOH H H C₆H₅ 432 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ COOH Cl H H 433 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ COOH CN H H 434 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ COOH COOH H H 435 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ COOH COOCH₃ H H

TABLE 23 No. n R¹—Y— R² R³ R⁴ R⁵ R⁶ 436 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ COOH CONH₂ H H 437 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ COOH CH₃ H H 438 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ COOH CHCH₂ H H 439 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ COOH C₆H₁₁ H H 440 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ COOH COCH₃ H H 441 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ COOH COC₆H₅ H H 442 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ COOH C₆H₅ H H 443 0 4-CH₃CH(CH₃)C₆H₄O— COC₆H₅ COOH 2-Pyridyl H H

TABLE 24

No. n R^(1c) R^(1d) R² R³ R⁴ R⁵ R⁶ 444 0 CH₃S(O)₂ H COC₆H₅ COOH H H H 445 0 CH₃ H COC₆H₅ COOH H CH₃ CH₃ 446 0 C₂H₅ H COC₆H₅ COOH H CH₃ CH₃ 447 0 CH₂CH H COC₆H₅ COOH H CH₃ CH₃ 448 0 CH₃CHCH H COC₆H₅ COOH H CH₃ CH₃ 449 0 C₆H₅ H COC₆H₅ COOH H CH₃ CH₃ 450 0 2-Pyridyl H COC₆H₅ COOH H CH₃ CH₃ 451 0 C₆H₅ H COC₆H₅ COOH H CH₃ CH₃ 452 0 C₆H₅CO H COC₆H₅ COOH H CH₃ CH₃ 453 0 H H COC₆H₅ COOH H H H 454 0 H Cl COC₆H₅ COOH H H H 455 0 H NC COC₆H₅ COOH H H H 456 0 H HOC(O) COC₆H₅ COOH H H H 457 0 H CH₃OC(O) COC₆H₅ COOH H H H 458 0 H CH₃ COC₆H₅ COOH H H H 459 0 H CH₃O COC₆H₅ COOH H H H 460 0 H C₆H₅CH₂ COC₆H₅ COOH H H H

TABLE 25 No. n R^(1c) R^(1d) R² R³ R⁴ R⁵ R⁶ 461 0 H CH₂CH COC₆H₅ COOH H H H 462 0 H CH₃CHCH COC₆H₅ COOH H H H 463 0 H C₆H₅ COC₆H₅ COOH H H H 464 0 H 2-Pyridyl COC₆H₅ COOH H H H 465 0 CH₃ CH₃ COC₆H₅ COOH H H H 466 0 C₂H₅ CH₃ COC₆H₅ COOH H H H 467 0 CH₂CH CH₃ COC₆H₅ COOH H H H 468 0 CH₃CHCH CH₃ COC₆H₅ COOH H H H 469 0 C₆H₅ CH₃ COC₆H₅ COOH H H H 470 0 2-Pyridyl CH₃ COC₆H₅ COOH H H H 471 0 CH₃ CH₃ CH₂C₆H₅ COOH CH₃ H H 472 0 CH₃ CH₃ CH₂C₆H₅ COOH H CH₃ CH₃ 473 0 CH₃ CH₃ CH₂C₆H₅ COOH CH₃ CH₃ CH₃ 474 0 CH₃ CH₃ C₆H₅ COOH CH₃ CH₃ CH₃ 475 0 CH₃ CH₃ S(O)₂C₆H₅ COOH CH₃ CH₃ CH₃ 476 0 CH₃ CH₃ 2-Thiazolyl COOH CH₃ CH₃ CH₃ 477 0 C₆H₅ C₆H₅ COC₆H₅ COOH H H H 478 0 C₆H₅CO H COC₆H₅ COOH H H H 479 0 CH₃CO H COC₆H₅ COOH H H H 480 0 CH₃NHC(O) H COC₆H₅ COOH H H H 481 0 CH₃S H COC₆H₅ COOH H H H 482 1 CH₂CH H COC₆H₅ COOH H CH₃ CH₃ 483 1 CH₃CHCH H COC₆H₅ COOH H CH₃ CH₃ 484 1 C₆H₅ H COC₆H₅ COOH H CH₃ CH₃

TABLE 26 No. n R^(1c) R^(1d) R² R³ R⁴ R⁵ R⁶ 485 1 2-Pyridyl H COC₆H₅ COOH H CH₃ CH₃ 486 1 C₆H₅ H COC₆H₅ COOH H CH₃ CH₃ 487 1 C₆H₅CO H COC₆H₅ COOH H CH₃ CH₃ 488 1 CH₃CO H COC₆H₅ COOH H CH₃ CH₃ 489 1 CH₃NHC(O) H COC₆H₅ COOH H CH₃ CH₃ 490 1 CH₃S H COC₆H₅ COOH H CH₃ CH₃ 491 0 CH₃CO H COC₆H₅ COOH H CH₃ CH₃ 492 0 CH₃NHC(O) H COC₆H₅ COOH H CH₃ CH₃ 493 0 CH₃S H COC₆H₅ COOH H CH₃ CH₃ 494 0 CH₃S(O)₂ H COC₆H₅ COOH H CH₃ CH₃ 495 1 H H COC₆H₅ COOH H H H 496 1 H CH₃ COC₆H₅ COOH H H H 497 1 H C₂H₅ COC₆H₅ COOH H H H 498 1 H CH₂CH COC₆H₅ COOH H H H 499 1 H CH₃CHCH COC₆H₅ COOH H H H 500 1 H C₆H₅ COC₆H₅ COOH H H H 501 1 H 2-Pyridyl COC₆H₅ COOH H H H 502 1 CH₃ CH₃ COC₆H₅ COOH H H H 503 1 C₂H₅ CH₃ COC₆H₅ COOH H H H 504 1 CH₂CH CH₃ COC₆H₅ COOH H H H 505 1 CH₃CHCH CH₃ COC₆H₅ COOH H H H 506 1 C₆H₅ CH₃ COC₆H₅ COOH H H H 507 1 2-Pyridyl CH₃ COC₆H₅ COOH H H H 508 1 CH₃ CH₃ CH₂C₆H₅ COOH H CH₃ CH₃

TABLE 27 No. n R^(1c) R^(1d) R² R³ R⁴ R⁵ R⁶ 509 1 CH₃ CH₃ CH₂C₆H₅ COOH CH₃ H H 510 1 CH₃ CH₃ CH₂C₆H₅ COOH CH₃ CH₃ CH₃ 511 1 CH₃ CH₃ C₆H₅ COOH CH₃ CH₃ CH₃ 512 1 CH₃ CH₃ S(O)₂C₆H₅ COOH CH₃ CH₃ CH₃ 513 1 CH₃ CH₃ 2-Thiazolyl COOH CH₃ CH₃ CH₃ 514 1 C₆H₅ C₆H₅ COC₆H₅ COOH H H H 515 1 C₆H₅CO H COC₆H₅ COOH H H H 516 1 CH₃CO H COC₆H₅ COOH H H H 517 1 CH₃NHC(O) H COC₆H₅ COOH H H H 518 1 CH₃S H COC₆H₅ COOH H H H 519 1 CH₃S(O)₂ H COC₆H₅ COOH H H H 520 1 CH₃ H COC₆H₅ COOH H CH₃ CH₃ 521 1 C₂H₅ H COC₆H₅ COOH H CH₃ CH₃ 522 2 C₆H₅ H COC₆H₅ COOH H CH₃ CH₃ 523 2 2-Pyridyl H COC₆H₅ COOH H CH₃ CH₃ 524 2 C₆H₅ H COC₆H₅ COOH H CH₃ CH₃ 525 2 C₆H₅CO H COC₆H₅ COOH H CH₃ CH₃ 526 2 CH₃CO H COC₆H₅ COOH H CH₃ CH₃ 527 2 CH₃NHC(O) H COC₆H₅ COOH H CH₃ CH₃ 528 2 CH₃S H COC₆H₅ COOH H CH₃ CH₃ 529 2 CH₃S(O)₂ H COC₆H₅ COOH H CH₃ CH₃ 530 1 CH₃ CH₃ COC₆H₅ CH₂CH₂F H CH₃ CH₃ 531 1 CH₃S(O)₂ H COC₆H₅ COOH H CH₃ CH₃

TABLE 28 No. n R^(1c) R^(1d) R² R³ R⁴ R⁵ R⁶ 532 2 H H COC₆H₅ COOH H H H 533 2 H CH₃O COC₆H₅ COOH H H H 534 2 H CH₃ COC₆H₅ COOH H H H 535 2 H C₂H₅ COC₆H₅ COOH H H H 536 2 H CH₂CH COC₆H₅ COOH H H H 537 2 H CH₃CHCH COC₆H₅ COOH H H H 538 2 H C₆H₅ COC₆H₅ COOH H H H 539 2 H 2-Pyridyl COC₆H₅ COOH H H H 540 2 CH₃ CH₃ COC₆H₅ COOH H H H 541 2 C₂H₅ CH₃ COC₆H₅ COOH H H H 542 2 CH₂CH CH₃ COC₆H₅ COOH H H H 543 2 CH₃CHCH CH₃ COC₆H₅ COOH H H H 544 2 C₆H₅ CH₃ COC₆H₅ COOH H H H 545 2 2-Pyridyl CH₃ COC₆H₅ COOH H H H 546 2 CH₃ CH₃ CH₂C₆H₅ COOH H CH₃ CH₃ 547 2 CH₃ CH₃ CH₂C₆H₅ COOH CH₃ H H 548 2 CH₃ CH₃ CH₂C₆H₅ COOH CH₃ CH₃ CH₃ 549 2 CH₃ CH₃ C₆H₅ COOH CH₃ CH₃ CH₃ 550 2 CH₃ CH₃ S(O)₂C₆H₅ COOH CH₃ CH₃ CH₃ 551 2 CH₃ CH₃ 2-Thiazolyl COOH CH₃ CH₃ CH₃ 552 2 C₆H₅ C₆H₅ COC₆H₅ COOH H H H 553 2 C₆H₅CO H COC₆H₅ COOH H H H 554 2 CH₃CO H COC₆H₅ COOH H H H 555 2 CH₃NHC(O) H COC₆H₅ COOH H H H

TABLE 29 No. n R^(1c) R^(1d) R² R³ R⁴ R⁵ R⁶ 556 2 CH₃S H COC₆H₅ COOH H H H 557 2 CH₃S(O)₂ H COC₆H₅ COOH H H H 558 2 CH₃ H COC₆H₅ COOH H CH₃ CH₃ 559 2 C₂H₅ H COC₆H₅ COOH H CH₃ CH₃ 560 2 CH₂CH H COC₆H₅ COOH H CH₃ CH₃ 561 2 CH₃CHCH H COC₆H₅ COOH H CH₃ CH₃ 562 1 CH₃ CH₃ COC₆H₅ COC₆H₅ H CH₃ CH₃ 563 1 CH₃ CH₃ COC₆H₅ COCH₃ H CH₃ CH₃ 564 1 CH₃ CH₃ COC₆H₅ C(NOH)CH₃ H CH₃ CH₃ 565 1 CH₃ CH₃ COC₆H₅ CHO H CH₃ CH₃ 566 1 CH₃ CH₃ COC₆H₅ CH₂OC(O)NH₂ H CH₃ CH₃ 567 1 CH₃ CH₃ COC₆H₅ CH₂OC(O)CH₃ H CH₃ CH₃ 568 1 CH₃ CH₃ COC₆H₅ CH₂OC(O)C₆H₅ H CH₃ CH₃ 569 1 CH₃ CH₃ COC₆H₅ CH₂COOH H CH₃ CH₃ 570 1 CH₃ CH₃ COC₆H₅ CH₂COOH H CH₃ CH₃ 571 1 CH₃ CH₃ COC₆H₅ CH₂CH₂OCH₂C₆H₅ H CH₃ CH₃ 572 1 CH₃ CH₃ COC₆H₅ CH₂F H CH₃ CH₃ 573 1 CH₃ CH₃ COC₆H₅ CH₂NH₂ H CH₃ CH₃ 574 1 CH₃ CH₃ COC₆H₅ CH₂CH₂NH₂ H CH₃ CH₃ 575 1 CH₃ CH₃ COC₆H₅ CH₂CH₂NHCHO H CH₃ CH₃ 576 1 CH₃ CH₃ COC₆H₅ CH₂CH₂NHCOOCH₃ H CH₃ CH₃ 577 1 CH₃ CH₃ COC₆H₅ CH₂CH₂N(CH₃)₂ H CH₃ CH₃ 578 1 CH₃ CH₃ COC₆H₅ CH₂CH₂NHCH₃ H CH₃ CH₃ 579 1 CH₃ CH₃ COC₆H₅ CH₂CH_(2NHCH) ₂C₆H₅ H CH₃ CH₃

TABLE 30 No. n R^(1c) R^(1d) R² R³ R⁴ R⁵ R⁶ 580 1 CH₃ CH₃ COC₆H₅ CH₂SH H CH₃ CH₃ 581 1 CH₃ CH₃ COC₆H₅ CH₂CH₂SH H CH₃ CH₃ 582 1 CH₃ CH₃ COC₆H₅ CH₂SCH₃ H CH₃ CH₃ 583 1 CH₃ CH₃ COC₆H₅ CH₂S(O)₂CH₃ H CH₃ CH₃ 584 1 CH₃ CH₃ COC₆R₅ CH₂S(O)CH₃ H CH₃ CH₃ 585 1 CH₃ CH₃ COC₆H₅ CONHCH(CH₂COOH)COOH H CH₃ CH₃ 586 1 CH₃ CH₃ COC₆H₅ CONHCH(CH₃)COOH H CH₃ CH₃ 587 1 CH₃ CH₃ COC₆H₅ CONHCH(CHCH₂(CH₃)₂)COOH H CH₃ CH₃ 588 1 CH₃ CH₃ COC₆R₅ CONHCH(CH₂OH)COOH H CH₃ CH₃ 589 1 CH₃ CH₃ COC₆H₅ CONHCH(CH₂CH₂SCH₃)COOH H CH₃ CH₃ 590 1 CH₃ CH₃ COC₆H₅ CONHCH((CH₂)₄NH₂)COOH H CH₃ CH₃ 591 1 CH₃ CH₃ COC₆H₅ CONHCH(C₆H₅)COOH H CH₃ CH₃ 592 1 CH₃ CH₃ COC₆H₅ CONHCH(CH₂CONH₂)COOH H CH₃ CH₃ 593 1 CH₃ CH₃ COC₆H₅ CONH₂ H CH₃ CH₃ 594 1 CH₃ CH₃ COC₆H₅ CH₂CONH₂ H CH₃ CH₃ 595 1 CH₃ CH₃ COC₆H₅ CONHCH₃ H CH₃ CH₃ 596 1 CH₃ CH₃ COC₆H₅ CONHOH H CH₃ CH₃ 597 1 CH₃ CH₃ COC₆H₅ CON(CH₃)₂ H CH₃ CH₃ 598 1 CH₃ CH₃ COC₆H₅ CONHC₆H₅ H CH₃ CH₃

TABLE 31

No. n R^(1e) R^(1f) R² R³ R⁴ R⁵ R⁶ 599 0 CH₃O C₆H₅ COC₆H₅ COOH H H H 600 0 H₂N C₆H₅ COC₆H₅ COOH H H H 601 0 CH₃C(O)NH C₆H₅ COC₆H₅ COOH H H H 602 0 2-Thienyl C₆H₅ COC₆H₅ COOH H H H 603 0 C₆H₅ OH CH₂C₆H₅ COOH H H H 604 0 C₆H₅ OH COCH₂C₆H₅ COOH H H H 605 0 C₆H₅ OH CH₂CH₂C₆H₅ COOH H H H 606 0 C₆H₅ OH C₆H₅ COOH H H H 607 0 C₆H₅ OH S(O)₂C₆H₅ COOH H H H 608 0 F C₆H₅ COC₆H₅ COOH H H H 609 0 Cl C₆H₅ COC₆H₅ COOH H H H 610 0 NC C₆H₅ COC₆H₅ COOH H H H 611 0 HOC(O) C₆H₅ COC₆H₅ COOH H H H 612 0 CH₃OC(O) C₆H₅ COC₆H₅ COOH H H H 613 0 (CH₃)₂NC(O) C₆H₅ COC₆H₅ COOH H H H 614 0 HO C₆H₅ COC₆H₅ COOH H H H 615 0 CH₃ C₆H₅ COC₆H₅ COOH H H H

TABLE 32 No. n R^(1e) R^(1f) R² R³ R⁴ R⁵ R⁶ 616 0 C₂H₅ C₆H₅ COC₆H₅ COOH H H H 617 0 CH₂CH C₆H₅ COC₆H₅ COOH H H H 618 0 C₆H₁₁ C₆H₅ COC₆H₅ COOH H H H 619 0 C₅H₉ C₆H₅ COC₆H₅ COOH H H H 620 0 C₄H₇ C₆H₅ COC₆H₅ COOH H H H 621 0 C₆H₅ C₆H₅ COC₆H₅ COOH H H H 622 0 C₆H₅ OH COC₆H₅ CONHCH(C₆H₅)COOH CH₃ CH₃ CH₃ 623 0 C₆H₅ OH COC₆H₅ CONHCH(CH₂CONH₂)COOH CH₃ CH₃ CH₃ 624 1 OH C₆H₅ COC₆H₅ COOH H H H 625 1 C₆H₅ OH COC₆H₅ CONH₂ CH₃ H H 626 1 C₆H₅ OH COC₆H₅ COOH H CH₃ CH₃ 627 1 C₆H₅ OH COC₆H₅ CONH₂ CH₃ CH₃ CH₃ 628 2 OH C₆H₅ COC₆H₅ COOH H H H 629 2 C₆H₅ OH COC₆H₅ CONH₂ CH₃ H H 630 2 C₆H₅ OH COC₆H₅ COOH H CH₃ CH₃ 631 0 C₆H₅ OH 2-Thiazolyl COOH H H H 632 0 C₆H₅ OH COC₆H₅ COOH CH₃ H H 633 0 C₆H₅ OH COC₆H₅ COOH H CH₃ CH₃ 634 0 C₆H₅ OH COC₆H₅ COOH CH₃ CH₃ CH₃ 635 0 C₆H₅ OH COC₆H₅ COOH CH₃ CH₃ CH₃ 636 0 C₆H₅ OH COC₆H₅ CO(O)CH₂C₆H₅ CH₃ CH₃ CH₃ 637 0 C₆H₅ OH COC₆H₅ CO(O)C₂H₅ CH₃ CH₃ CH₃

TABLE 33 No. n R^(1e) R^(1f) R² R³ R⁴ R⁵ R⁶ 638 0 C₆H₅ OH COC₆H₅ CONH₂ CH₃ CH₃ CH₃ 639 0 C₆H₅ OH COC₆H₅ CH₂CONH₂ CH₃ CH₃ CH₃ 640 0 C₆H₅ OH COC₆H₅ CONHCH₃ CH₃ CH₃ CH₃ 641 0 C₆H₅ OH COC₆H₅ CONHOH CH₃ CH₃ CH₃ 642 0 C₆H₅ OH COC₆H₅ CON(CH₃)₂ CH₃ CH₃ CH₃ 643 0 C₆H₅ OH COC₆H₅ CONHC₆H₅ CH₃ CH₃ CH₃ 644 0 C₆H₅ OH COC₆H₅ COC₆H₅ CH₃ CH₃ CH₃ 645 0 C₆H₅ OH COC₆H₅ COCH₃ CH₃ CH₃ CH₃ 646 0 C₆H₅ OH COC₆H₅ C(NOH)CH₃ CH₃ CH₃ CH₃ 647 0 C₆H₅ OH COC₆H₅ CHO CH₃ CH₃ CR₃ 648 0 C₆H₅ OH COC₆H₅ CH₂OC(O)NH₂ CH₃ CH₃ CH₃ 649 0 C₆H₅ OH COC₆H₅ CH₂OC(O)CH₃ CH₃ CH₃ CH₃ 650 0 C₆H₅ OH COC₆H₅ CH₂OC(O)C₆H₅ CH₃ CH₃ CH₃ 651 0 C₆H₅ OH COC₆H₅ CH₂COOH CH₃ CH₃ CH₃ 652 0 C₆H₅ OH COC₆H₅ CONHCH(CH₂COOH)COOH CH₃ CH₃ CH₃ 653 0 C₆H₅ OH COC₆H₅ CONHCH(CH₃)COOH CH₃ CH₃ CH₃ 654 0 C₆H₅ OH COC₆H₅ CONHCH(CHCH₂(CH₃)₂)COOH CH₃ CH₃ CH₃ 655 0 C₆H₅ OH COC₆H₅ CONHCH(CH₂OH)COOH CH₃ CH₃ CH₃ 656 0 C₆H₅ OH COC₆H₅ CONHCH(CH₂CH₂SCH₃)COOH CH₃ CH₃ CH₃ 657 0 C₆H₅ OH COC₆H₅ CONHCH((CH₂)₄NH₂)COOH CH₃ CH₃ CH₃ 658 2 C₆H₅ OH COC₆H₅ CONH₂ CH₃ CH₃ CH₃

TABLE 34

R³, No. n R¹—Y— R² R⁴ R⁵ R⁶ 659 0 H₂NNH— CH₂C₆H₅ O H CH₂COOH 660 0 H₂N— CH₂C₆H₅ O H CH₂COOH 661 0 ClCO— CH₂C₆H₅ O H CH₂COOH 662 0 ClCHCH— CH₂C₆H₅ O H CH₂COOH 663 0 ClSO₂— CH₂C₆H₅ O H CH₂COOH 664 0 HOS(O)₂— CH₂C₆H₅ O H CH₂COOH 665 0 NCS(O)₂— CH₂C₆H₅ O H CH₂COOH 666 0 CH₃OS(O)₂— CH₂C₆H₅ O H CH₂COOH 667 0 H₂NS(O)₂— CH₂C₆H₅ O H CH₂COOH 668 0 HO— CH₂C₆H₅ O H CH₂COOH 669 0 O₂NO— CH₂C₆H₅ O H CH₂COOH 670 0 H₂NC(O)O— CH₂C₆H₅ O H CH₂COOH 671 0 HS— CH₂C₆H₅ O H CH₂COOH 672 0 HOS— CH₂C₆H₅ O H CH₂COOH 673 0 CH₃(O)S— CH₂C₆H₅ O H CH₂COOH

TABLE 35 R³, No. n R¹—Y— R² R⁴  R⁵ R⁶ 674 0 OHC— CH₂C₆H₅ O H CH₂COOH 675 0 O₂NCHCH— CH₂C₆H₅ O H CH₂COOH 676 0 CH₂CHCHCH— CH₂C₆H₅ O H CH₂COOH 677 0 CH₃OCHCH— CH₂C₆H₅ O H CH₂COOH 678 0 CH₃C(O)CHCH— CH₂C₆H₅ O H CH₂COOH 679 0 CH₂CH— CH₂C₆H₅ O H CH₂COOH 680 0 ClCH₂CH₂— CH₂C₆H₅ O H CH₂COOH 681 0 NCCH₂— CH₂C₆H₅ O H CH₂COOH 682 0 O₂NCH₂— CH₂C₆H₅ O H CH₂COOH 683 0 CH₃OC(O)CH₂— CH₂C₆H₅ O H CH₂COOH 684 0 HOC(O)CH₂— CH₂C₆H₅ O H CH₂COOH 685 0 CH₃COCH₂— CH₂C₆H₅ O H CH₂COOH 686 0 H₂NCH₂ CH₂C₆H₅ O H CH₂COOH 687 0 HOCH₂— CH₂C₆H₅ O H CH₂COOH 688 0 HONH— CH₂C₆H₅ O H CH₂COOH 689 0 CH₃C(O)NCl— CH₂C₆H₅ O H CH₂COOH 690 0 O₂NNH— CH₂C₆H₅ O H CH₂COOH 691 0 CH₃ONH— CH₂C₆H₅ O H CH₂COOH 692 0 CH₂CHS(O)— CH₂C₆H₅ O H CH₂COOH 693 0 CH₂CHS(O)₂— CH₂C₆H₅ O H CH₂COOH 694 0 2-Thiazolylsulfonyl CH₂C₆H₅ O H CH₂COOH 695 0 CH₂CHCH(OH)— CH₂C₆H₅ O H CH₂COOH

TABLE 36 No. n R¹—Y— R² R³, R⁴ R⁵ R⁶ 696 0 C₆H₁₁O— CH₂C₆H₅ O H CH₂COOH 697 0 C₆H₁₁S— CH₂C₆H₅ O H CH₂COOH 698 0 C₆H₁₁NH— CH₂C₆H₅ O H CH₂COOH 699 0 C₆H₁₁CHCH— CH₂C₆H₅ O H CH₂COOH 700 0 C₆H₁₁S(O)— CH₂C₆H5 O H CH₂COOH 701 0 NCCO— CH₂C₆H₅ O H CH₂COOH 702 0 NCCHCH— CH₂C₆H₅ O H CH₂COOH 703 0 NCS— CH₂C₆H₅ O H CH₂COOH 704 0 C₆H₁₁S(O)₂— CH₂C₆H₅ O H CH₂COOH 705 0 HOC(O)C(O)— CH₂C₆H₅ O H CH₂COOH 706 0 H₃COC(O)NH— CH₂C₆H₅ O H CH₂COOH 707 0 HOC(O)CHCH— CH₂C₆H₅ O H CH₂COOH 708 0 HOC(O)CH(OH)— CH₂C₆H₅ O H CH₂COOH 709 0 HOO— CH₂C₆H₅ O H CH₂COOH 710 0 HOC(O)— CH₂C₆H₅ O H CH₂COOH 711 0 CH₃OC(O)CHCH CH₂C₆H₅ O H CH₂COOH 712 0 CH₃OC(O)SCHCH CH₂C₆H₅ O H CH₂COOH 713 0 (HO)₂CH— CH₂C₆H₅ O H CH₂COOH 714 0 CH₃O— CH₂C₆H₅ O H CH₂COOH 715 0 CH₃S— CH₂C₆H₅ O H CH₂COOH 716 0 CH₃NH— CH₂C₆H₅ O H CH₂COOH 717 0 CH₃CO— CH₂C₆H₅ O H CH₂COOH

TABLE 37 No. n R¹-Y- R₂ R³, R⁴ R⁵ R⁶ 718 0 CH₃CHCH— CH₂C₆H₅ O H CH₂COOH 719 0 C₆H₅C(O)— CH₂C₆H₅ O H CH₂COOH 720 0 CH₃C(O)— CH₂C₆H₅ O H CH₂COOH 721 0 CH₃S(O)₂— CH₂C₆H₅ O H CH₂COOH 722 0 NCCH(OH)— CH₂C₆H₅ O H CH₂COOH 723 0 CH₃OC(O)CH(OH)— CH₂C₆H₅ O H CH₂COOH 724 0 CH₃C(O)CH(OH)— CH₂C₆H₅ O H CH₂COOH 725 0 CH₃CH(OH)— CH₂C₆H₅ O H CH₂COOH 726 0 CH₂CHO— CH₂C₆H₅ O H CH₂COOH 727 0 CH₂CHS— CH₂C₆H₅ O H CH₂COOH 728 0 CH₂CHNH— CH₂C₆H₅ O H CH₂COOH 729 0 CH₂CHCO— CH₂C₆H₅ O H CH₂COOH 730 0 CH₂CHCH₂— CH₂C₆H₅ O H CH₂COOH 731 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂CH(C₂H₅)C₂H₅ O H CH₂COOH 732 0 4-CH₃CH(CH₃)C₆H₄O— CH₂F O H CH₂COOH 733 0 4-CH₃CH(CH₃)C₆H₄O— CH₂OH O H CH₂COOH 734 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂OH O H CH₂COOH 735 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂CH₂OH O H CH₂COOH 736 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂CH₂CH₂OH O H CH₂COOH 737 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂CH₂CH₂CH₂OH O H CH₂COOH 738 0 4-CH₃CH(CH₃)C₆H₄O— CH(OH)CH₂OH O H CH₂COOH 739 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH(OH)CH₂OH O H CH₂COOH 740 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH(OH)CH₂CH₂OH O H CH₂COOH

TABLE 38 No. n R¹—Y— R² R³, R⁴ R⁵ R⁶ 741 0 C₆H₁₁CH(OH)— CH₂C₆H₅ O H CH₂COOH 742 0 CH₃C(O)O— CH₂C₆H₅ O H CH₂COOH 743 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂CH(CH₃)C₂H₅ O H CH₂COOH 744 0 CH₃C(O)NH— CH₂C₆H₅ O H CH₂COOH 745 0 H₂NC(O)— CH₂C₆H₅ O H CH₂COOH 746 0 C₆H₅CH₂CH₂— CH₂C₆H₅ O H CH₂COOH 747 0 2-Pyridylethenyl CH₂C₆H₅ O H CH₂COOH 748 0 C₆H₅CHCH— CH₂C₆H₅ O H CH₂COOH 749 0 CH₃C(O)C(O)— CH₂C₆H₅ O H CH₂COOH 750 0 CH₃C(O)C(O)— CH₂CH₂C₆H₅ O H CH₂COOH 751 0 Cyclohexanecarbonyl CH₂C₆H₅ O H CH₂COOH 752 0 2-Thienylcarbonyl CH₂C₆H₅ O H CH₂COOH 753 0 CH₃OC(O)— CH₂C₆H₅ O H CH₂COOH 754 0 CH₃OC(O)CHCH— CH₂C₆H₅ O H CH₂COOH 755 0 CH₃C(O)NHCHCH— CH₂C₆H₅ O H CH₂COOH 756 0 CH₃SCHCH— CH₂C₆H₅ O H CH₂COOH 757 0 CH₃S(O)CHCH— CH₂C₆H₅ O H CH₂COOH 758 0 CH₃S(O)₂CHCH— CH₂C₆H₅ O H CH₂COOH 759 0 4-CH₃CH(CH₃)C₆H₄O— H O H CH₂COOH 760 0 4-CH₃CH(CH₃)C₆H₄O— CH₃ O H CH₂COOH 761 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₃ O H CH₂COOH 762 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂CH₃ O H CH₂COOH

TABLE 39 No. n R¹—Y— R² R³, R⁴ R⁵ R⁶ 763 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂CH₂CH₃ O H CH₂COOH 764 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂CH₂CH₂CH₃ O H CH₂COOH 765 0 4-CH₃CH(CH₃)C₆H₄O— CH(CH₃)CH₃ O H CH₂COOH 766 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH(CH₃)CH₃ O H CH₂COOH 767 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂CH(CH₃)CH₃ O H CH₂COOH 768 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂CH₂CH(CH₃)CH₃ O H CH₂COOH 769 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH(CH₃)C₂H₅ O H CH₂COOH 770 0 4-CH₃CH(CH₃)C₆H₄O— CH(CH₂OH)COOH O H CH₂COOH 771 0 4-CH₃CH(CH₃)C₆H₄O— CH(CH₂COOH)COOH O H CH₂COOH 772 0 4-CH₃CH(CH₃)C₆H₄O— CH(CH₂CONH₂)COOH O H CH₂COOH 773 0 4-CH₃CH(CH₃)C₆H₄O— CH(CH₂CH₂COOH)COOH O H CH₂COOH 774 0 4-CH₃CH(CH₃)C₆H₄O— CH(CH₂CH₂CONH₂)COOH O H CH₂COOH 775 0 4-CH₃CH(CH₃)C₆H₄O— CH(4-Imidazolylmethyl)- O H CH₂COOH COOH 776 0 4-CH₃CH(CH₃)C₆H₄O— CH(CH(C₂H₅)CH₃)COOH O H CH₂COOH 777 0 4-CH₃CH(CH₃)C₆H₄O— CH(CH₂CH(CH₃)CH₃)COOH O H CH₂COOH 778 0 4-CH₃CH(CH₃)C₆H₄O— CH(CH₂CH₂SCH₃)COOH O H CH₂COOH 779 0 4-CH₃CH(CH₃)C₆H₄O— CH(CH(OH)CH₃)COOH O H CH₂COOH 780 0 4-CH₃CH(CH₃)C₆H₄O— CH(CH₂—(4-HO)C₆H₅)- O H CH₂COOH COOH 781 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂CH(OH)CH₂CH₂OH O H CH₂COOH 782 0 4-CH₃CH(CH₃)C₆H₄O— CH₂OC(O)NH₂ O H CH₂COOH 783 0 4-CH₃CH(CH₃)C₆H₄O— CH₂OC(O)CH₃ O H CH₂COOH 784 0 4-CH₃CH(CH₃)C₆H₄O— CH₂COOH O H CH₂COOH

TABLE 40 No. n R¹—Y— R² R³, R⁴ R⁵ R⁶ 785 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOH O H CH₂COOH 786 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂CH₂COOH O H CH₂COOH 787 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂CH₂CH₂COOH O H CH₂COOH 788 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂CH₂CH₂CH₂COOH O H CH₂COOH 789 0 4-CH₃CH(CH₃)C₆H₄O— CH₂COOCH₃ O H CH₂COOH 790 0 4-CH₃CH(CH₃)C₆H₄O— CH₂COOC2H₅ O H CH₂COOH 791 0 4-CH₃CH(CH₃)C₆H₄O— CH₂COO—n—C₃H₇ O H CH₂COOH 792 0 4-CH₃CH(CH₃)C₆H₄O— CH₂COO-i-C₃H₇ O H CH₂COOH 793 0 4-CH₃CH(CH₃)C₆H₄O— CH₂COOC₆H₅ O H CH₂COOH 794 0 4-CH₃CH(CH₃)C₆H₄O— CH₂COOCH₂C₆H₅ O H CH₂COOH 795 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 796 0 4-CH₃CH(CH₃)C₆H₄O— CH(CH₃)COOH O H CH₂COOH 797 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CONH₂ O H CH₂COOH 798 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CONHOH O H CH₂COOH 799 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CONHCH₃ O H CH₂COOH 800 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CONHC₂H₅ O H CH₂COOH 801 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CONH-n-C₃H₇ O H CH₂COOH 803 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CONH-i-C₃H₇ O H CH₂COOH 803 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CON(CH₃)₂ O H CH₂COOH 804 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CON(n-C₃H₇₎ ₂ O H CH₂COOH 805 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CON(C₂H₅)₂ O H CH₂COOH 806 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CONHC₆H₅ O H CH₂COOH

TABLE 41 No. n R¹—Y— R² R³, R⁴ R⁵ R⁶ 807 0 4-CH₃CR(CH₃)C₆H₄O— CH₂CH₂COOCH₃ O H CH₂COOH 808 0 4-CH₃CH(CH₃)C₆H₄O— Cyclopentyl O H CH₂COOH 809 0 4-CH₃CH(CH₃)C₆H₄O— Cyclohexyl O H CH₂COOH 810 0 4-CH₃CH(CH₃)C₆H₄O— CH₂C₆H₅ O H CH₂COOH 811 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂C₆H₅ O H CH₂COOH 812 0 4-CH₃CH(CH₃)C₆H₄O— CH₂C₆H₁₁ O H CH₂COOH 813 0 4-CH₃CH(CH₃)C₆H₄O— CH(CH₃)C₆H₅ O H CH₂COOH 814 0 4-CH₃CH(CH₃)C₆H₄O— 2-Thienylmethyl O H CH₂COOH 815 0 4-CH₃CH(CH₃)C₆H₄O— 2-Furfuryl O H CH₂COOH 816 0 4-CH₃CH(CH₃)C₆H₄O— 2-Pyranylmethyl O H CH₂COOH 817 0 4-CH₃CH(CH₃)C₆H₄O— 1-Isobenzofurylmethyl O H CH₂COOH 818 0 4-CH₃CH(CH₃)C₆H₄O— 2-Pyrrolylmethyl O H CH₂COOH 819 0 4-CH₃CH(CH₃)C₆H₄O— 1-Imidazolylmethyl O H CH₂COOH 820 0 4-CH₃CH(CH₃)C₆H₄O— 1-Pyrazolylmethyl O H CH₂COOH 821 0 4-CH₃CH(CH₃)C₆H₄O— CH(CH₂C₆H₅)COOH O H CH₂COOH 822 0 4-CH₃CH(CH₃)C₆H₄O— CH(3-Indolylmethyl)COOH O H CH₂COOH 823 0 4-CH₃CH(CH₃)C₆H₄O— CH(1-C₃H₇)COOH O H CH₂COOH 824 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CN O H CH₂COOH 825 0 4-CH₃CH(CH₃)C₆H₄O— CH₂NO₂ O H CH₂COOH 826 0 4-CH₃CH(CH₃)C₆H₄O— CH₂COCH₃ O H CH₂COOH 827 0 4-CH₃CH(CH₃)C₆H₄O— CH₂C(OCH₂)₂CH₃ O H CH₂COOH 828 0 4-CH₃CH(CH₃)C₆H₄O— CH₂C(SCH₃)₂CH₃ O H CH₂COOH

TABLE 42 No. n R¹—Y— R² R³, R⁴ R⁵ R⁶ 829 0 4-CH₃CH- C(NH)NH₂ O H CH₂COOH (CH₃)C₆- H₄O— 830 0 4-CH₃CH- CH₂C(NOH)CH₃ O H CH₂COOH (CH₃)C₆- H₄O— 831 0 4-CH₃CH- CH₂SH O H CH₂COOH (CH₃)C₆- H₄O— 832 0 4-CH₃CH- CH₂SO₃H O H CH₂COOH (CH₃)C₆- H₄O— 833 0 4-CH₃CH- CH₂S(O)₂CH₃ O H CH₂COOH (CH₃)C₆- H₄O— 834 0 4-CH₃CH- CH₂S(O)CH₃ O H CH₂COOH (CH₃)C₆- H₄O— 835 0 4-CH₃CH- CH₂S(O)₂NH₃ O H CH₂COOH (CH₃)C₆- H₄O— 836 0 4-CH₃CH- Cyclobutyl O H CH₂COOH (CH₃)C₆- H₄O— 837 0 4-CH₃CH- CH₂OCH₃ O H CH₂COOH (CH₃)C₆- H₄O— 838 0 4-CH₃CH- CH₂CH₂OCH₃ O H CH₂COOH (CH₃)C₆- H₄O— 839 0 4-CH₃CH- CH₂CH₂CH₂OCH₃ O H CH₂COOH (CH₃)C₆- H₄O— 840 0 4-CH₃CH- CH₂SCH₃ O H CH₂COOH (CH₃)C₆- H₄O— 841 0 4-CH₃CH- CH₂CH₂SCH₃ O H CH₂COOH (CH₃)C₆- H₄O— 842 0 4-CH₃CH- CH₂CH₂CH₂SCH₃ O H CH₂COOH (CH₃)C₆- H₄O— 843 0 4-CH₃CH- CHCH₂ O H CH₂COOH (CH₃)C₆- H₄O— 844 0 4-CH₃CH- CH₂CHCH₂ O H CH₂COOH (CH₃)C₆- H₄O— 845 0 4-CH₃CH- CCH O H CH₂COOH (CH₃)C₆- H₄O— 846 0 4-CH₃CH- Cyclopropyl O H CH₂COOH (CH₃)C₆- H₄O— 847 0 4-CH₃CH- 2-Thiazolyl O H CH₂COOH (CH₃)C₆- H₄O— 848 0 4-CH₃CH- 4-Imidazolyl O H CH₂COOH (CH₃)C₆- H₄O— 849 0 4-CH₃CH- 3-Pyrazolyl O H CH₂COOH (CH₃)C₆- H₄O— 850 0 4-CH₃CH- 3-Isoxazolyl O H CH₂COOH (CH₃)C₆- H₄O—

TABLE 43 No. n R¹—Y— R² R³, R⁴ R⁵ R⁶ 851 0 4-CH₃CH(CH₃)C₆H₄O— 5-Isothiazolyl O H CH₂COOH 852 0 4-CH₃CH(CH₃)C₆H₄O— 2-Pyrimidinyl O H CH₂COOH 853 0 4-CH₃CH(CH₃)C₆H₄O— 3-(1,2,4-Triazolyl) O H CH₂COOH 854 0 4-CH₃CH(CH₃)C₆H₄O— 2-Pyridyl O H CH₂COOH 855 0 4-CH₃CH(CH₃)C₆H₄O— 2-Benzoxazolyl O H CH₂COOH 856 0 4-CH₃CH(CH₃)C₆H₄O— 3-Benzothienyl O H CH₂COOH 857 0 4-CH₃CR(CH₃)C₆H₄O— 2-Benzofuryl O H CH₂COOH 858 0 4-CH₃CH(CH₃)C₆H₄O— 5-Indolyl O H CH₂COOH 859 0 4-CH₃CH(CH₃)C₆H₄O— 2-Pyrazinyl O H CH₂COOH 860 0 4-CH₃CH(CH₃)C₆H₄O— 3-Quinolyl O H CH₂COOH 861 0 4-CH₃CH(CH₃)C₆H₄O— 3-Isothiazolylmethyl O H CH₂COOH 862 0 4-CH₃CH(CH₃)C₆H₄O— 3-Jsoxazolylmethyl O H CH₂COOH 863 0 4-CH₃CH(CH₃)C₆H₄O— 2-Pyridylmethyl O H CH₂COOH 864 0 4-CH₃CH(CH₃)C₆H₄O— 2-Pyrazinylmethyl O H CH₂COOH 865 0 4-CH₃CH(CH₃)C₆H₄O— 2-Pyrimidinylmethyl O H CH₂COOH 866 0 4-CH₃CH(CH₃)C₆H₄O— 3-Pyridazinylmethyl O H CH₂COOH 867 0 4-CH₃CH(CH₃)C₆H₄O— 1-Isoindolylmethyl O H CH₂COOH 868 0 4-CH₃CH(CH₃)C₆H₄O— 2-Jndolylmethyl O H CH₂COOH 869 0 4-CH₃CH(CH₃)C₆H₄O— 3-(1H-Indazolyl)methyl O H CH₂COOH 870 0 4-CH₃CH(CH₃)C₆H₄O— 2-Purinylmethyl O H CH₂COOH 871 0 4-CH₃CH(CH₃)C₆H₄O— 1-Isoquinolylmethyl O H CH₂COOH 872 0 4-CH₃CH(CH₃)C₆H₄O— 2-Quinolylmethyl O H CH₂COOH

TABLE 44 No. n R¹—Y— R² R³, R⁴ R⁵ R⁶ 873 0 4-CH₃CH(CH₃)C₆H₄O— 1-Phthalazinylmethyl O H CH₂COOH 874 0 4-CH₃CH(CH₃)C₆H₄O— 2-Naphthylidinylmethyl O H CH₂COOH 875 0 4-CH₃CH(CH₃)C₆H₄O— 2-Quinoxalinylmethyl O H CH₂COOH 876 0 4-CH₃CH(CH₃)C₆H₄O— 2-Quinazolinylmethyl O H CH₂COOH 877 0 4-CH₃CH(CH₃)C₆H₄O— 3-Cinnolinylmethyl O H CH₂COOH 878 0 4-CH₃CH(CH₃)C₆H₄O— 2-Oxazolylmethyl O H CH₂COOH 879 0 4-CH₃CH(CH₃)C₆H₄O— 2-Thiazolylmethyl O H CH₂COOH 880 0 4-CH₃CH(CH₃)C₆H₄O— 2-Benzo[b]furylmethyl O H CH₂COOH 881 0 4-CH₃CH(CH₃)C₆H₄O— 2-Benzo[b]thienylmethyl O H CH₂COOH 882 0 4-CH₃CH(CH₃)C₆H₄O— 3-(1,2,4-Triazinyl)methyl O H CH₂COOH 883 0 4-CH₃CH(CH₃)C₆H₄O— 2-Benz[d]imidazolylmethyl O H CH₂COOH 884 0 4-CH₃CH(CH₃)C₆H₄O— 2-Benz[d]oxazolylmethyl O H CH₂COOH 885 0 4-CH₃CH(CH₃)C₆H₄O— Phenyl O H CH₂COOH 886 0 4-CH₃CH(CH₃)C₆H₄O— 2-Naphthyl O H CH₂COOH 887 0 4-C₆H₅CH₂OC₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 888 0 4-HO₂CC₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 889 0 4-H₃COC(O)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 890 0 4-H₂NC(O)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 891 0 4-HONHC(O)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 892 0 4-H₃CNHC(O)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 893 0 4-(H₃C)₂NC(O)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 894 0 4-O₂NC₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH

TABLE 45 No. n R¹—Y— R² R³, R⁴ R⁵ R⁶ 895 0 4-H₂NC₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 896 0 4-H₃CNHC₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 897 0 4-(H₃C)₂NC₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 898 0 4-OHCC₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 899 0 4-HONCHC₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 900 0 4-OHCNHC₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 901 0 4-CH₃CH(CH₃)C₆H₄O— 5-Tetrazolyl O H CH₂COOH 902 0 4-CH₃CH(CH₃)C₆H₄O— Methylsulfonyl O H CH₂COOH 903 0 4-CH₃CH(CH₃)C₆H₄O— Benzenesulfonyl O H CH₂COOH 904 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CONHCH₂C₆H₅ O H CH₂COOH 905 0 4-FC₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 906 0 2-CH₃C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 907 0 3-CH₃C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 908 0 4-CH₃C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 909 0 2,4-(CH₃)₂C₆H₃O— CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 910 0 3,4-(CH₃)₂C₆H₃O— CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 911 0 2,3-(CH₃)₂C₆H₃O— CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 912 0 3,5-(CH₃)₂C₆H₃O— CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 913 0 3,6-(CH₃)₂C₆H₃O— CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 914 0 2,6-(CH₃)₂C₆H₃O— CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 915 0 2,5-(CH₃)₂C₆H₃O— CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 916 0 2,4,6-(CH₃)₃C₆H₂O— CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH

TABLE 46 No. n R¹—Y— R² R³, R⁴ R⁵ R⁶ 917 0 2,3,5-(CH₃)₃C₆H₂O— CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 918 0 4-CH(OCH₃)₂C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 919 0 4-CH(SCH₃)₂C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CH₂CpOH 920 0 2,4,5-(CH₃)₃C₆H₂O— CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 921 0 2,5,6-(CH₃)₃C₆H₂O— CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 922 0 4-HOC₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 923 0 4-H₃COC₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 924 0 4-C₂H₅OC₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 925 0 4-CH₃CH(CH₃)OC₆H₄O— CH₂CH₂CO9CH₂C₆H₅ O H CH₂COOH 926 0 4-C₆H₅OC₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 927 0 2-Benzoxazolylamino CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 928 0 3-Benzothienylamino CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 929 0 2-Benzofurylamino CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 930 0 5-Indolylamino CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 931 0 2-Pyrazinylamino CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 932 0 3-Ouinolylamino CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 933 0 5-Tetrazolylamino CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 934 0 2-Iniidazolylthioxy CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 935 0 2-Pyridylthioxy CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 936 0 2-Benzothiazolylthioxy CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 937 0 2-Benzothienylethenyl CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 938 0 2-Benzothienylethynyl CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH

TABLE 47 No. n R¹—Y— R² R³, R⁴ R⁵ R⁶ 939 0 2-Benzothienylmethyl CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 940 0 4-CH₃CH(CH₃)C₆H₄S(O)— CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 941 0 4-H₃CC(O)NHC₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 942 0 4-H₃COC(O)NHC₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 943 0 4-H₂NC(O)OC₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 944 0 4-HSC₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 945 0 4-H₃CSC₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 946 0 4-H₃CS(O)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 947 0 4-H₃CS(O)₂C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 948 0 3,4-(OCH₂O)C₆H₃O— CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 949 0 3,4-(CH₂CH₂CH₂)C₆H₃O— CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 950 0 4-HO₃SC₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 951 0 4-NCC₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 952 0 4-H₂NC(NH)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 953 0 2-Pyridylamino CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 954 0 3-Isoxazoloxy CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 955 0 2-Imidazoloxy CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 956 0 2-Benzimidazoloxy CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 957 0 2-Thiazoloxy CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 958 0 5-Benzo[b]thienyloxy CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 959 0 2-Thiazolylamino CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 960 0 4-Imidazolylamino CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH

TABLE 48 No. n R^(1—Y—) R² R³, R⁴ R⁵ R⁶ 961 0 3-Pyrazolylamino CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 962 0 3-Isoxazolylamino CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 963 0 5-Isothiazolylamino CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 964 0 2-Pyrimidinylamino CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 965 0 3-(1,2,4-Triazolyl)amino CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 966 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CH(CH₃)- COOH 967 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CH(C₆H₅)- COOH 968 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H C(CH₃)₂- COOH 969 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H C(C₂H₄)- COOH 970 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H C(C₃H₆)- COOH 971 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H C(C₄H₈)- COOH 972 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H C(C₅H₁₀)- COOH 973 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H C(O)COOH 974 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H C(NOH)- COOH 975 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H C(OCH₃)₂- COOH 976 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H C(SCH₃)₂- COOH 977 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CH(CH₂- OH)COOH 978 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CH(NH₂)- COOH 979 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CH(NHC- HO)COOH 980 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CH₂CH₂- COOH 981 0 4-CH₃CH(CH₃)C₆H₄S(O)₂ CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 982 0 4-CH₃CH(CH₃)C₆H₄OS(O)₂ CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH

TABLE 49 No. n R¹—Y— R² R³, R⁴ R⁵ R⁶ 983 0 4-CH₃CH(CH₃)C₆H₄S— CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 984 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CH(OH)- COOH 985 0 4-CH₃CH(CH₃)C₆H₄NH— CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 986 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 987 0 4-CH₃CH(CH₃)C₆H₄CH- CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH (OH)— 988 0 4-CH₃CH(CH₃)C₆H₄OCH₂— CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 989 0 4-CH₃CH(CH₃)C₆H₄OC(O)— CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 990 0 4-CH₃CH(CH₃)C₆H₄CH₂OC- CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH (O)— 991 0 4-CH₃CH(CH₃)C₆H₄NHC- CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH (O)— 992 0 4-CH₃CH(CH₃)C₆H₄OC- CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH (O)NH— 993 0 4-CH₃CH(CH₃)C₆H₄CH₂OC- CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH (O)NH— 994 0 4-CH₃CH(CH₃)C₆H₄- CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH CONH— 995 0 4-CH₃CH(CH₃)C₆H₄CH₂- CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH CONH— 996 0 4-CH₃CH(CH₃)C₆H₄CH₂- CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH CO— 997 0 4-CH₃CH(CH₃)C₆H₄CH₂- CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH OCH₂— 998 0 4-CH₃CH(CH₃)C₆H₄C- CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH (NOH)— 999 0 4-CH₃CH(CH₃)C₆H₄CHCH— CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 1000 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CH(OCH₃)- COOH 1001 0 4-CH₃CH(CH₃)C₆H₄CH₂— CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 1002 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CHFCOOH 1003 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CF₂COOH 1004 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CH₂CH₂- NHCH₂C₆H₅

TABLE 50 No. n R¹—Y— R² R³, R⁴ R⁵ R⁶ 1005 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CH₂CH₂SH 1006 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CH₂CH₂SCH₃ 1007 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CH₂CH₂SO2CH₃ 1008 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CH₂CH₂S(O)CH₃ 1009 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CH₂CONH₂ 1010 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COdCH₂C₆H₅ O H CH₂CONHCH- (CH₃)COOH 1011 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CH₂CONHCH- (CH₂CONH₂)- COOH 1012 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CH₂CONHCH₃ 1013 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CH₂CONHOH 1014 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CH₂CON(CH₃)₂ 1015 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CH₂CONHC₆H₅ 1016 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CH₂COC₆H₅ 1017 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CH₂COCH₃ 1018 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CH₂C(OCH₃)₂- CH₃ 1019 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CH₂CH(OCH₃)₂ 1020 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CH₂C(NOR)CH₃ 1021 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CH₂CH(OH)- COOH 1022 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CH(OH)CH₂- COOH 1023 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CH₂CHFCOOH 1024 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CH₂CH₂OH 1025 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CH₂CH₂OCH₃ 1026 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CH₂CH₂OC₆H₅

TABLE 51 No. n R¹—Y— R² R³, R⁴ R⁵ R⁶ 1027 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CH₂CH₂- OCH₂C₆H₅ 1028 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CH₂CH₂F 1029 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H⁵ O H CH₂CH₂NH₂ 1030 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CH₂CH₂- NHCHO 1031 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CH₂CH₂- NHCOOCH₃ 1032 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CH₂CH₂- N(CH₃) 1033 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CH₂CH₂- NH(CH₃) 1034 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O CHCH₂ H 1035 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O COCH₃ H 1036 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O COC₆- H H₅ 1037 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O C₆H₅ H 1038 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O CH₂- H C₆H₅ 1039 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O Cl CH₂COOH 1040 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O CN CH₂COOH 1041 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O COOH CH₂COOH 1042 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O CH₂- CH₂COOH COOH 1043 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O CONH₂ CH₂COOH 1044 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O CONH- CH₂COOH CH₃ 1045 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O CH₃ CH₂COOH 1046 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O CHCH₂ CH₂COOH 1047 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O COCH₃ CH₂COOH 1048 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O COC₆- CH₂COOH H₅

TABLE 52 No. n R¹—Y— R² R³, R⁴ R⁵ R⁶ 1049 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O C₆H₅ CH₂- COOH 1050 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O CH₂C₆H₅ CH₂- COOH 1051 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CH₂- CHO 1052 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CH₂- CH₂O- CONH₂ 1053 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CH₂- CH₂O- COCH₃ 1054 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CH₂- CH₂O- COC₆- H₅ 1055 1 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CH₂- COOH 1056 2 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H CH₂- COOH 1057 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O H H 1058 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O Cl H 1059 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O CN H 1060 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O COOH H 1061 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O CONH₂ H 1062 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O CONHCH₃ H 1063 0 4-CH₃CH(CH₃)C₆H₄O— CH₂CH₂COOCH₂C₆H₅ O CH₃ H

TABLE 53 No. n R^(1c) R^(1d) R² R³, R⁴ R⁵ R⁶ 1064 0 CH₃ CH₃ CH₂CONH₂ O H CH₂COOH 1065 0 CH₃ CH₃ CH₂CONHOH O H CH₂COOH 1066 0 CH₃ CH₃ CH₂CONHCH₃ O H CH₂COOH 1067 0 CH₃ CH₃ CH₂CONHC2H₅ O H CH₂COOH 1068 0 CH₃ CH₃ CH₂CONH-n-C₃- O H CH₂COOH H₇ 1069 0 CH₃ CH₃ CH₂CONH-i-C₃- O H CH₂COOH H₇ 1070 0 CH₃ CH₃ CH₂CON(CH₃)₂ O H CH₂COOH 1071 0 CH₃ CH₃ CH₂CON(n-C₃- O H CH₂COOH H₇)₂ 1072 0 CH₃ CH₃ CH₂CON(C2H₅)₂ O H CH₂COOH 1073 0 CH₃ CH₃ CH₂CONHC₆H₅ O H CH₂COOH 1074 0 CH₃ CH₃ CH₂CH₂- O H CH₂COOH COOCH₃ 1075 0 CH₃ CH₃ CH₂CH₂- O H CH₂COOH COOCH₂C₆H₅ 1076 0 CH₃ CH₃ CH(CH₃)COOH O H CH₂CO9H 1077 0 CH₃ CH₃ CH(CH₂OH)- O H CH₂COOH COOH 1078 0 CH₃ CH₃ CH(CH₂COOH)- O H CH₂COOH COOH 1079 0 CH₃ CH₃ CH(CH₂CONH₂- O H CH₂COOH )COOH 1080 0 CH₃ CH₃ CH(CH₂CH₂- O H CH₂COOH COOH)COOH 1081 0 CH₃ CH₃ CH₂COOH O H CH₂COOH 1082 0 CH₃ CH₃ CH₂CH₂COOH O H CH₂COOH 1083 0 CH₃ CH₃ CH₂CH₂CH₂- O H CH₂COOH COOH 1084 0 CH₃ CH₃ CH₂CH₂CH₂- O H CH₂COOH CH₂COOH 1085 0 CH₃ CH₃ CH₂CH₂CH₂- O H CH₂COOH CH₂CH₂COOH

TABLE 54 No. n R^(1c) R^(1d) R² R³, R⁴ R⁵ R⁶ 1086 0 CH₃ CH₃ CH₂COOCH₃ O H CH₂COOH 1087 0 CH₃ CH₃ CH₂COOC₂H₅ O H CH₂COOH 1088 0 CH₃ CH₃ CH₂COO-n-C₃H₇ O H CH₂COOH 1089 0 CH₃ CH₃ CH₂COO-i-C₃H₇ O H CH₂COOH 1090 0 CH₃ CH₃ CH₂COOC₆H₅ O H CH₂COOH 1091 0 CH₃ CH₃ CH₂COOCH₂C₆- O H CH₂COOH H₅ 1092 0 CH₃ CH₃ H O H CH₂COOH 1093 0 CH₃ CH₃ CH₂F O H CH₂COOH 1094 0 CH₃ CH₃ CH(i-C₃H₇)- O H CH₂COOH COOH 1095 0 CH₃ CH₃ CH₂CN O H CH₂COOH 1096 0 CH₃ CH₃ CH₂NO₂ O H CH₂COOH 1097 0 CH₃ CH₃ CH₂COCH₃ O H CH₂COOH 1098 0 CH₃ CH₃ CH₂C(OCH₃)- O H CH₂COOH ₂CH₃ 1099 0 CH₃ CH₃ CH₂C(SCH₃)- O H CH₂COOH ₂CH₃ 1100 0 CH₃ CH₃ C(NH)NH₂ O H CH₂COOH 1101 0 CH₃ CH₃ CH₂C(NOH)CH₃ O H CH₂COOH 1102 0 CH₃ CH₃ CH₂SH O H CH₂COOH 1103 0 CH₃ CH₃ CH₂SO₃H O H CH₂COOH 1104 0 CH₃ CH₃ CH₂S(O)₂CH₃ O H CH₂COOH 1105 0 CH₃ CH₃ CH₂S(O)CH₃ O H CH₂COOH 1106 0 CH₃ CH₃ CH₂S(O)₂NH₂ O H CH₂COOH 1107 0 CH₃ CH₃ CH₂SO₃CH₃ O H CH₂COOH

TABLE 55 No. n R^(1c) R^(1d) R² R³, R⁴ R⁵ R⁶ 1108 0 CH₃ CH₃ CH₂OCH₃ O H CH₂CCOH 1109 0 CH₃ CH₃ CH₂CH₂OCH₃ O H CH₂COOH 1110 0 CH₃ CH₃ CH₂CH₂CH₂- O H CH₂COOH OCH₃ 1111 0 CH₃ CH₃ CH₂SCH₃ O H CH₂COOH 1112 0 CH₃ CH₃ CH₂CH₂SCH₃ O H CH₂COOH 1113 0 CH₃ CH₃ CH₂CH₂CH₂- O H CH₂COOH SCH₃ 1114 0 CH₃ CH₃ CHCH₂ O H CH₂COOH 1115 0 CH₃ CH₃ CH₂CHCH₂ O H CH₂COCH 1116 0 CH₃ CH₃ S(O)₂C₆C₅ O H CH₂COOH 1117 0 CH₃ CH₃ Cyclopropyl O H CH₂COOH 1118 0 CH₃ CH₃ Cyclobutyl O H CH₂COOH 1119 0 CH₃ CH₃ Cyclopentyl O H CH₂COOH 1120 0 CH₃ CH₃ Cyclohexyl O H CH₂COOH 1121 0 CH₃ CH₃ CH(CH₂CH₂- O H CH₂COOH CONH₂)COOH 1122 0 CH₃ CH₃ CH(4-Imidazolyl- O H CH₂COOH methyl)COOH 1123 0 CH₃ CH₃ CH(CH(C₂H₅- O H CH₂COOH )CH₃)COOH 1124 0 CH₃ CH₃ CH(CH₂CH(CH₃- O H CH₂COOH )CH₃)COOH 1125 0 CH₃ CH₃ CH(CH₂CH₂- O H CH₂COOH SCH₃)COOH 1126 0 CH₃ CH₃ CH(CH(OH)CH₃- O H CH₂COOH )COOH 1127 0 CH₃ CH₃ CH(CH₂—(4- O H CH₂COOH HO)C₆H₅)COOH 1128 0 CH₃ CH₃ CH(CH₂C₆- O H CH₂COOH H₅)COOH 1129 0 CH₃ CH₃ CH(3-Indolyl- O H CH₂COOH methyl)COOH 1130 0 CH₃ CH₃ S(O)₂CH₃ O H CH₂COOH

TABLE 56 No. n R^(1c) R^(1d) R² R³, R⁴ R⁵ R⁶ 1141 0 CH₃ CH₃ CH₂C₆H₅ O H CH₂COOH 1142 0 CH₃ CH₃ CH₂CH₂C₆H₅ O H 1143 0 CH₃ CH₃ CH₂C₆H₁₁ O H 1144 0 CH₃ CH₃ CH(CH₃)C₆H₅ O H CH₂COOH 1145 0 CH₃ CH₃ 2-Thienylmethyl O H CH₂COOH 1146 0 CH₃ CH₃ 2-Furfuryl O H CH₂COOH 1147 0 CH₃ CH₃ 2-Pyranylmethyl O H CH₂COOH 1148 0 CH₃ CH₃ 1-Isobenzo- O H CH₂COOH furanylmethyl 1149 0 CH₃ CH₃ 2-Pyrrolylmethyl O H CH₂COOH 1150 0 CH₃ CH₃ 1-Imidazolyl- O H CH₂COOH methyl 1151 0 CH₃ CH₃ 1-Pyrazolyl- O H CH₂COOH methyl 1152 0 CH₃ CH₃ 3-Isothiazolyl- O H CH₂COOH methyl 1153 0 CH₃ CH₃ 3-Isoxazolyl- O H CH₂COOH methyl 1154 0 CH₃ CH₃ 2-Pyridylmethyl O H CH₂COOH 1155 0 CH₃ CH₃ 2-Pyrazinyl- O H CH₂COOH methyl 1156 0 CH₃ CH₃ 2-Pyrimidinyl- O H CH₂COOH methyl 1157 O CH₃ CH₃ 3-Pyridazinyl- O H CH₂COOH methyl 1158 0 CH₃ CH₃ 1-Isoindolyl- O H CH₂COOH methyl 1159 0 CH₃ CH₃ 2-Indolylmethyl O H CH₂COOH 1160 0 CH₃ CH₃ 3-(1H-Indazolyl)- O H CH₂COOH methyl 1161 0 CH₃ CH₃ 2-Purinylmethyl O H CH₂COOH 1162 0 CH₃ CH₃ 1-Isoquinolyl- O H CH₂COOH methyl

TABLE 57 No. n R^(1c) R^(1d) R² R³, R⁴ R⁵ R⁶ 1163 0 CH₃ CH₃ 2-Quinolylmethyl O H CH₂COOH 1164 0 CH₃ CH₃ 1-Phthalazinyl- O H CH₂COOH methyl 1165 0 CH₃ CH₃ 2-Naphthylidinyl- O H CH₂COOH methyl 1166 0 CH₃ CH₃ 2-Quinoxalinyl- O H CH₂COOH methyl 1167 0 CH₃ CH₃ 2-Quinazolinyl- O H CH₂COOH methyl 1168 0 CH₃ CH₃ 3-Cinnolinyl- O H CH₂COOH methyl 1169 0 CH₃ CH₃ 2-Oxazolylmethyl O H CH₂COOH 1170 0 CH₃ CH₃ 2-Thiazolyl- O H CH₂COOH methyl 1171 0 CH₃ CH₃ 2-Benzo[b]- O H CH₂COOH furylmethyl 1172 0 CH₃ CH₃ 2-Benzo[b]- O H CH₂COOH thienylmethyl 1173 0 CH₃ CH₃ 3-(1,2,4-Tria- O H CH₂COOH zinyl)methyl 1174 0 CH₃ CH₃ 2-Benz[d]- O H CH₂COOH imidazolylmethyl 1175 0 CH₃ CH₃ 2-Benz[d]- O H CH₂COOH oxazolylmethyl 1176 0 CH₃ CH₃ Phenyl O H CH₂COOH 1177 0 CH₃ CH₃ 2-Naphthyl O H CH₂COOH 1178 0 CH₃ CH₃ 2-Thiazolyl O H CH₂COOH 1179 0 CH₃ CH₃ 4-Imidazolyl O H CH₂COOH 1180 0 CH₃ CH₃ 3-Pyrazolyl O H CH₂COOH 1181 0 CH₃ CH₃ 3-Isoxazolyl O H CH₂COOH 1182 0 CH₃ CH₃ 5-Isothiazolyl O H CH₂COOH 1183 0 CH₃ CH₃ 2-Pyrimidinyl O H CH₂COOH 1184 0 CH₃ CH₃ 3-(1,2,4- O H CH₂COOH Triazolyl)

TABLE 58 No. n R^(1c) R^(1d) R² R³, R⁴ R⁵ R⁶ 1185 0 CH₃ CH₃ 2-Pyridyl O H CH₂COOH 1186 0 CH₃ CH₃ 2-Benzoxa- O H CH₂COOH zolyl 1187 0 CH₃ CH₃ 3-Benzo- O H CH₂COOH thienyl 1188 0 CH₃ CH₃ 2-Benzo- O H CH₂COOH furinyl 1189 0 CH₃ CH₃ 5-Indolyl O H CH₂COOH 1190 0 CH₃ CH₃ 2-Pyrazinyl O H CH₂COOH 1191 0 CH₃ CH₃ 3-Quinolyl O H CH₂COOH 1192 0 CH₃ CH₃ 5-Tetrazolyl O H CH₂COOH 1193 0 CH₃ CH₃ Methyl- O H CH₂COOH sulfonyl 1194 0 CH₃ CH₃ Benzene- O H CH₂COOH sulfonyl 1195 0 CH₃ CH₃ CH₂CONH- O H CH₂COOH CH₂C₆H₅ 1196 0 CH₃ CH₃ CH₂CH₂CO- O H CHFCOOH OCH₂C₆H₅ 1197 0 CH₃ CH₃ CH₂CH₂CO- O H CF₂COOH OCH₂C₆H₅ 1198 0 CH₃ CH₃ CH₂CH₂O- O H CH(OH)COOH OCH₂C₆H₅ 1199 0 CH₃ CH₃ CH₂CH₂CO- O H CH(OCH₃)COOH OCH₂C₆H₅ 1200 0 CH₃ CH₃ CH₂CH₂CO- O H CH(CH₃)COOH OCH₂C₆H₅ 1201 0 CH₃ CH₃ CH₂CH₂CO- O H CH(C₆H₅)COOH OCH₂C₆H₅ 1202 0 CH₃ CH₃ CH₂CH₂CO- O H C(tH3)₂COOH OCH₂C₆H₅ 1203 0 CH₃ CH₃ CH₂CH₂CO- O H C(C2H₄)COOH OCH₂C₆H₅ 1204 0 CH₃ CH₃ CH₂CH₂CO- O H C(C₃H₆)COOH OCH₂C₆H₅ 1205 0 CH₃ CH₃ CH₂CH₂CO- O H C(C₄H₈)COOH OCH₂C₆H₅ 1206 0 CH₃ CH₃ CH₂CH₂CO- O H C(C₅H₁₀)COOH OCH₂C₆H₅

TABLE 59 No. n R^(1c) R^(1d) R² R³, R⁴ R⁵ R⁶ 1207 0 CH₃ CH₃ CH₂CH₂- O H COCOOH COOCH₂C₆H₅ 1208 0 CH₃ CH₃ CH₂CH₂- O H C(NOH)COOH COOCH₂C₆H₅ 1209 0 CH₃ CH₃ CH₂CH₂- O H C(OCH₃)₂- COOCH₂C₆H₅ COOH 1210 0 CH₃ CH₃ CH₂CH₂- O H C(SCH₃)₂- COOCH₂C₆H₅ COOH 1211 0 CH₃ CH₃ CH₂CH₂- O H CH(CH₂OH)- COOCH₂C₆H₅ COOH 1212 0 CH₃ CH₃ CH₂CH₂- O H CH(NH₂)- COOCH₂C₆H₅ COOH 1213 0 CH₃ CH₃ CH₂CH₂- O H CH(NHCHO)- COOCH₂C₆H₅ COOH 1214 0 CH₃ CH₃ CH₂CH₂- O H CH₂CH₂COOH COOCH₂C₆H₅ 1215 0 CH₃ CH₃ CH₂CH₂- O H CH₂CH(OH)- COOCH₂C₆H₅ COOH 1216 0 CH₃ CH₃ CH₂CH₂- O H CH(OH)CH₂- COOCH₂C₆H₅ COOH 1217 0 CH₃ CH₃ CH₂CH₂- O H CH₂- COOCH₂C₆H₅ CHFCOOH 1218 0 CH₃ CH₃ CH₂CH₂- O H CH₂CH₂OH COOCH₂C₆H₅ 1219 0 CH₃ CH₃ CH₂CH₂- O H CH₂CH₂OCH₃ COOCH₂C₆H₅ 1220 0 CH₃ CH₃ CH₂CH₂- O H CH₂CH₂- COOCH₂C₆H₅ OC₆H₅ 1221 0 CH₃ CH₃ CH₂CH₂- O H CH₂CH₂- COOCH₂C₆H₅ OCH₂C₆H₅ 1222 0 CH₃ CH₃ CH₂CH₂- O H CH₂CH₂F COOCH₂C₆H₅ 1223 0 CH₃ CH₃ CH₂CH₂- O H CH₂CH₂NH₂ COOCH₂C₆H₅ 1224 0 CH₃ CH₃ CH₂CH₂- O H CH₂CH₂- COOCH₂-C₆H₅ NHCHO 1225 0 CH₃ CH₃ CH₂CH₂- O H CH₂CH₂- COOCH₂C₆H₅ NHCOOCH₃ 1226 0 CH₃ CH₃ CH₂CH₂- O H CH₂CH₂- COOCH₂C₆H₅ N(CH₃)₂ 1227 0 CH₃ CH₃ CH₂CH₂- O H CH₂CH₂- COOCH₂C₆H₅ NH(CH₃) 1228 0 CH₃ CH₃ CH₂CH₂- O H CH₂CH₂- COOCH₂C₆H₅ NHCH₂C₆H₅

TABLE 60 No. n R^(1c) R^(1d) R² R³, R⁴ R⁵ R⁶ 1229 0 CH₃ CH₃ CH₂CH₂COOCH₂C₆H₅ O H CH₂CH₂SH 1230 0 CH₃ CH₃ CH₂CH₂COOCH₂C₆H₅ O H CH₂CH₂SCH₃ 1231 0 CH₃ CH₃ CH₂CH₂COOCH₂C₆H₅ O H CH₂CH₂S(O)₂CH₃ 1232 0 CH₃ CH₃ CH₂CH₂COOCH₂C₆H₅ O H CH₂CH₂S(O)CH₃ 1233 0 CH₃ CH₃ CH₂CH₂COOCH₂C₆H₅ O H CH₂CONH₂ 1234 0 CH₃ CH₃ CH₂CH₂COOCH₂C₆H₅ O H CH₂CONCH(CH₃)COOH 1235 0 CH₃ CH₃ CH₂CH₂COOCH₂C₆H₅ O H CH₂CONHCH₃ 1236 0 CH₃ CH₃ CH₂CH₂COOCH₂C₆H₅ O H CH₂CONHOH 1237 0 CH₃ CH₃ CH₂CH₂COOCH₂C₆H₅ O H CH₂CON(CH₃)₂ 1238 0 CH₃ CH₃ CH₂CH₂COOCH₂C₆H₅ O H CH₂CONHC₆H₅ 1239 0 CH₃ CH₃ CH₂CH₂COOCH₂C₆H₅ O H CH₂COC₆H₅ 1240 0 CH₃ CH₃ CH₂CH₂COOCH₂C₆H₅ O H CH₂COCH₃ 1241 0 CH₃ CH₃ CH₂CH₂COOCH₂C₆H₅ O H CH4C(OCH₃)₂CH₃ 1242 0 CH₃ CH₃ CH₂CH₂COOCH₂C₆H₅ O H CH₂CH(OCH₃)₂ 1243 0 CH₃ CH₃ CH₂CH₂COOCH₂C₆H₅ O H CH₂C(NOH)CH₃ 1244 0 CH₃ CH₃ CH₂CH₂COOCH₂C₆H₅ O H CH₂CHO 1245 0 CH₃ CH₃ CH₂CH₂COOCH₂C₆H₅ O H CH₂CH₂OC(O)NH₂ 1246 0 CH₃ CH₃ CH₂CH₂COOCH₂C₆H₅ O H CH₂CH₂OC(O)CH₃ 1247 0 CH₃ CH₃ CH₂CH₂COOCH₂C₆H₅ O H CH₂CH₂OC(O)C₆H₅ 1248 0 CH₃ CH₃ CH₂CH₂COOCH₂C₆H₅ O Cl CH₂COOH 1249 0 CH₃ CH₃ CH₂CH₂COOCH₂C₆H₅ O CN CH₂COOH 1250 0 CH₃ CH₃ CH₂CH₂COOCH₂C₆H₅ O CO- CH₂COOH OH

TABLE 61 No. n R^(1c) R^(1d) R² R³, R⁴ R⁵ R⁶ 1251 0 CH₃ CH₃ CH₂CH₂COOCH₂C₆H₅ O CH₂COOH CH₂COOH 1252 0 CH₃ CH₃ CH₂CH₂COOCH₂C₆H₅ O CONH₂ CH₂COOH 1253 0 CH₃ CH₃ CH₂CH₂COOCH₂C₆H₅ O CONHCH₃ CH₂COOH 1254 0 CH₃ CH₃ CH₂CH₂COOCH₂C₆H₅ O CH₃ CH₂COOH 1255 0 CH₃ CH₃ CH₂CH₂COOCH₂C₆H₅ O CHCH₂ CH₂COOH 1256 0 CH₃ CH₃ CH₂CH₂COOCH₂C₆H₅ O COCH₃ CH₂COOH 1257 0 CH₃ CH₃ CH₂CH₂COOCH₂C₆H₅ O COC₆H₅ CH₂COOH 1258 0 CH₃ CH₃ CH₂CH₂COOCH₂C₆H₅ O C₆H₅ CH₂COOH 1259 0 CH₃ CH₃ CH₂CH₂COOCH₂C₆H₅ O CH₂C₆H₅ CH₂COOH 1260 0 H H CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 1261 0 H Cl CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 1262 0 H NC CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 1263 0 H HOC(O) CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 1264 0 H CH₃OC(O) CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 1265 0 H H₂NC(O) CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 1266 0 H CH₃ CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 1267 0 H C₆H₅CH₂ CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 1268 0 H CH₃CONH CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 1269 0 H CH₃O CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 1270 0 H CH₂CH CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 1271 0 H CH₃CHCH CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 1272 0 H C₆H₅ CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH

TABLE 62 No. n R^(1c) R^(1d) R² R³, R⁴ R⁵ R⁶ 1273 0 H 2-Pyridyl CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 1274 0 Cl CH₃ CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 1275 0 NC CH₃ CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 1276 0 HOC(O) CH₃ CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 1277 0 CH₂OC(O) CH₃ CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 1278 0 H₂NC(O) CH₃ CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 1279 0 CH₃ CH₃ CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 1280 0 C2H₅ CH₃ CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 1281 0 CH₂CH CH₃ CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 1282 0 CH₃CHCH CH₃ CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 1283 0 C₆H₅ CH₃ CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 1284 0 2-Pyridyl CH₃ CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 1285 0 C₆H₅ C₆H₅ CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 1286 0 C₆H₅CO H CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 1287 0 CH₃CO H CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 1288 0 CH₃NHCO H CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 1289 0 CH₃S H CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 1290 0 CH₃S(O) H CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 1291 0 CH₃S(O)₂ H CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 1292 0 CH₃ H CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 1293 0 C2H₅ H CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH 1294 0 CH₂CH H CH₂CH₂COOCH₂C₆H₅ O H CH₂COOH

Table 63 No. n R^(1c) R^(1d) R² R³, R⁴ R⁵ R⁶ 1295 0 CH₃- H CH₂CH₂- O H CH₂COOH CHCH COOCH₂C₆H₅ 1296 0 C₆H₅ H CH₂CH₂- O H CH₂COOH COOCH₂C₆H₅ 1297 0 2- H CH₂CH₂- O H CH₂COOH Pyridyl COOCH₂C₆H₅ 1298 1 H H CH₂CH₂- O H CH₂COOH COOCH₂C₆H₅ 1299 1 CH₃ CH₃ CH₂CH₂- O H CH₂COOH COOCH₂C₆H₅ 1300 1 CH₃ H CH₂CH₂- O H CH₂COOH COOCH₂C₆H₅ 1301 1 C₆H₅ C₆H₅ CH₂CH₂- O H CH₂COOH COOCH₂C₆H₅ 1302 1 C₆H₅ H CH₂CH₂- O H CH₂COOH COOCH₂C₆H₅ 1303 2 H H CH₂CH₂- O H CH₂COOH COOCH₂C₆H₅ 1304 2 CH₃ CH₃ CH₂CH₂- O H CH₂COOH COOCH₂C₆H₅ 1305 2 CH₃ H CH₂CH₂- O H CH₂COOH COOCH₂C₆H₅ 1306 2 C₆H₅ C₆H₅ CH₂CH₂- O H CH₂COOH COOCH₂C₆H₅ 1307 2 C₆H₅ H CH₂CH₂- O H CH₂COOH COOCH₂C₆H₅

TABLE 64

No. n R^(1e) R^(1f) R² R³, R⁴ R⁵ R⁶ 1308 0 F C₆H₅ CH₂C₆H₅ O H CH₂COOH 1309 0 Cl C₆H₅ CH₂C₆H₅ O H CH₂COOH 1310 0 NC C₆H₅ CH₂C₆H₅ O H CH₂COOH 1311 0 HOC(O) HOC(O) CH₂C₆H₅ O H CH₂COOH 1312 0 CH₃OC(O) CH₃OC(O) CH₂C₆H₅ O H CH₂COOH 1313 0 (CH₃)₂NO (CH₃)₂NCO CH₂C₆H₅ O H CH₂COOH 1314 0 HO C₆H₅ CH₂C₆H₅ O H CH₂COOH 1315 0 CH₃ C₆H₅ CH₂C₆H₅ O H CH₂COOH 1316 0 C₂H₅ C₆H₅ CH₂C₆H₅ O H CH₂COOH 1317 0 CH₂CH C₆H₅ CH₂C₆H₅ O H CH₂COOH 1318 0 Cyclohexyl C₆H₅ CH₂C₆H₅ O H CH₂COOH 1319 0 Cyclopentyl C₆H₅ CH₂C₆H₅ O H CH₂COOH 1320 0 Cyclobutyl C₆H₅ CH₂C₆H₅ O H CH₂COOH 1321 0 C₆H₅ C₆H₅ CH₂C₆H₅ O H CH₂COOH 1322 0 CH₃OC(O) C₆H₅ CH₂C₆H₅ O H CH₂COOH

TABLE 65 No. n R^(1e) R^(1f) R² R³, R⁴ R⁵ R⁶ 1323 0 CH₃S C₆H₅ CH₂C₆H₅ O H CH₂COOH 1324 0 CH₃S(O) C₆H₅ CH₂C₆H₅ O H CH₂COOH 1325 0 CH₃S(O)₂ C₆H₅ CH₂C₆H₅ O H CH₂COOH 1326 0 H₂N C₆H₅ CH₂C₆H₅ O H CH₂COOH 1327 0 CH₃CONH C₆H₅ CH₂C₆H₅ O H CH₂COOH 1328 0 2-Thienyl C₆H₅ CH₂C₆H₅ O H CH₂COOH 1329 0 C₆H₅ HO CH₂C₆H₅ O H CHFCOOH 1330 0 C₆H₅ HO CH₂C₆H₅ O H CF2COOH 1331 0 C₆H₅ HO CH₂C₆H₅ O H CH(OH)- COOH 1332 0 C₆H₅ HO CH₂C₆H₅ O H CH(OCH₃- )COOH 1333 0 C₆H₅ HO CH₂C₆H₅ O H CH(CH₃- )COOH 1334 0 C₆H₅ HO CH₂C₆H₅ O H CH(C₆- H₅)COOH 1335 0 C₆H₅ HO CH₂C₆H₅ O H C(CH₃- )₂COOH 1336 0 C₆H₅ HO CH₂C₆H₅ O H C(C₂- H₄)COOH 1337 0 C₆H₅ HO CH₂C₆H₅ O H C(C₃- H₆)COOH 1338 0 C₆H₅ HO CH₂C₆H₅ O H C(C₄- H₈)COOH 1339 0 C₆H₅ HO CH₂C₆H₅ O H C(C₅- H₁₀)COOH 1340 0 C₆H₅ HO CH₂C₆H₅ O H COCOOH 1341 0 C₆H₅ HO CH₂C₆H₅ O H C(NOH)- COOH 1342 0 C₆H₅ HO CH₂C₆H₅ O H C(OCH₃- )₂COOH 1343 0 C₆H₅ HO CH₂C₆H₅ O H C(SCH₃- )₂COOH 1344 0 C₆H₅ HO CH₂C₆H₅ O H CH(CH₂- OH)COOH

TABLE 66 No. n R^(1e) R^(1f) R² R³, R⁴ R⁵ R⁶ 1345 0 C₆H₅ HO CH₂C₆H₅ O H CH(NH₂)COOH 1346 0 C₆H₅ HO CH₂C₆H₅ O H CH(NHCHO)- COOH 1347 0 C₆H₅ HO CH₂C₆H₅ O H CH₂CH₂COOH 1348 0 C₆H₅ HO CH₂C₆H₅ O H CH₂CH(OH)COOH 1349 0 C₆H₅ HO CH₂C₆H₅ O H CH(OH)CH₂COOH 1350 0 C₆H₅ HO CH₂C₆H₅ O H CH₂CHFCOOH 1351 0 C₆H₅ HO CH₂C₆H₅ O H CH₂CH₂OH 1352 0 C₆H₅ HO CH₂C₆H₅ O H CH₂CH₂OCH₃ 1353 0 C₆H₅ HO CH₂C₆H₅ O H CH₂CH₂OC₆H₅ 1354 0 C₆H₅ HO CH₂C₆H₅ O H CH₂CH₂OCH₂C₆H₅ 1355 0 C₆H₅ HO CH₂C₆H₅ O H CH₂CH₂F 1356 0 C₆H₅ HO CH₂C₆H₅ O H CH₂CH₂NH₂ 1357 0 C₆H₅ HO CH₂C₆H₅ O H CH₂CH₂NHCHO 1358 0 C₆H₅ HO CH₂C₆H₅ O H CH₂CH₂- NHCOOCH₃ 1359 0 C₆H₅ HO CH₂C₆H₅ O H CH₂CH₂N(CH₃)₂ 1360 0 C₆H₅ HO CH₂C₆H₅ O H CH₂CH₂NH(CH₃) 1361 0 C₆H₅ HO CH₂C₆H₅ O H CH₂CH₂- NHCH₂C₆H₅ 1362 0 C₆H₅ HO CH₂C₆H₅ O H CH₂CH₂SH 1363 0 C₆H₅ HO CH₂C₆H₅ O H CH₂CH₂SCH₃ 1364 0 C₆H₅ HO CH₂C₆H₅ O H CH₂CH₂S(O)₂CH₃ 1365 0 C₆H₅ HO CH₂C₆H₅ O H CH₂CH₂S(O)CH₃ 1366 0 C₆H₅ HO CH₂C₆H₅ O H CH₂CONH₂

Table 67 No. n R^(1e) R^(1f) R² R³, R⁴ R⁵ R⁶ 1367 0 C₆H₅ HO CH₂C₆H₅ O H CH₂CONHCH- (CH₃)COOH 1368 0 C₆H₅ HO CH₂C₆H₅ O H CH₂CONHCH₃ 1369 0 C₆H₅ HO CH₂C₆H₅ O H CH₂CONHOH 1370 0 C₆H₅ HO CH₂C₆H₅ O H CH₂CON(CH₃- )₂ 1371 0 C₆H₅ HO CH₂C₆H₅ O H CH₂CONHC₆- H₅ 1372 0 C₆H₅ HO CH₂C₆H₅ O H CH₂COC₆H₅ 1373 0 C₆H₅ HO CH₂C₆H₅ O H CH₂COCH₃ 1374 0 C₆H₅ HO CH₂C₆H₅ O H CH₂C(OCH₃- )₂CH₃ 1375 0 C₆H₅ HO CH₂C₆H₅ O H CH₂CH- (OCH₃)₂ 1376 0 C₆H₅ HO CH₂C₆H₅ O H CH₂C(NOH)- CH₃ 1377 0 C₆H₅ HO CH₂C₆H₅ O H CH₂CHO 1378 0 C₆H₅ HO CH₂C₆H₅ O H CH₂CH₂- OC(O)NH₂ 1379 0 C₆H₅ HO CH₂C₆H₅ O H CH₂CH₂- OC(O)CH₃ 1380 0 C₆H₅ HO CH₂C₆H₅ O H CH₂CH₂- OC(O)C₆H₅ 1381 0 C₆H₅ HO CH₂C₆H₅ O Cl CH₂COOH 1382 0 C₆H₅ HO CH₂C₆H₅ O CN CH₂COOH 1383 0 C₆H₅ HO CH₂C₆H₅ O COOH CH₂COOH 1384 0 C₆H₅ HO CH₂C₆H₅ O CH₂- CH₂COOH COOH 1385 0 C₆H₅ HO CH₂C₆H₅ O CONH₂ CH₂COOH 1386 0 C₆H₅ HO CH₂C₆H₅ O CONH- CH₂COOH CH₃ 1387 0 C₆H₅ HO CH₂C₆H₅ O CH₃ CH₂COOH 1388 0 C₆H₅ HO CH₂C₆H₅ O CHCH₂ CH₂COOH

TABLE 68 R³, No. n R^(1e) R^(1f) R² R⁴ R⁵ R⁶ 1389 0 C₆H₅ HO CH₂C₆H₅ O OCH₃ CH₂COOH 1390 0 C₆H₅ HO CH₂C₆H₅ O COC₆H₅ CH₂COOH 1391 0 C₆H₅ HO CH₂C₆H₅ O C₆H₅ CH₂COOH 1392 0 C₆H₅ HO CH₂C₆H₅ O CH₂C₆H₅ CH₂COOH 1393 1 HO C₆H₅ CH₂C₆H₅ O H CH₂COOH 1394 2 HO C₆H₅ CH₂C₆H₅ O H CH₂COOH 1395 0 HO C₆H₅ H O H CH₂COOH 1396 0 HO C₆H₅ CH₃ O H CH₂COOH 1397 0 HO C₆H₅ C₂H₅ O H CH₂COOH 1398 0 HO C₆H₅ CHCH₂ O H CH₂COOH 1399 0 HO C₆H₅ Cyclohexyl O H CH₂COOH 1400 0 HO C₆H₅ Cyclobutyl O H CH₂COOH 1401 0 HO C₆H₅ C₆H₅ O H CH₂COOH 1402 0 HO C₆H₅ S(O)₂CH₃ O H CH₂COOH 1403 0 HO C₆H₅ S(O)₂C₆H₅ O H CH₂COOH 1404 0 HO C₆H₅ 2-Thienyl O H CH₂COOH

TABLE 69

No. n R¹—Y— R² R³ R⁴ R⁵ R⁶ 3001 0 4-CH₃CH(CH₃)C₆H₄O— COCH₂CH₂CH(CH₃)₂ COOH H H H 3002 0 4-CH₃CH(CH₃)C₆H₄O— COCH₂CH₂CH(CH₃)₂ COOH H CH₃ CH₃ 3003 1 4-CH₃CH(CH₃)C₆H₄O— COCH₂CH₂CH(CH₃)₂ COOH H H H 3004 1 4-CH₃CH(CH₃)C₆H₄O— COCH₂CH₂CH(CH₃)₂ COOH H CH₃ CH₃ 3005 2 4-CH₃CH(CH₃)C₆H₄O— COCH₂CH₂CH(CH₃)₂ COOH H H H 3006 2 4-CH₃CH(CH₃)C₆H₄O— COCH₂CH₂CH(CH₃)₂ COOH H CH₃ CH₃ 3007 0 2,3-Dihydro-1H-inden-5-yloxy COCH₂CH₂CH(CH₃)₂ COOH H H H 3009 0 2,3-Dihydro-1H-inden-5-yloxy COCH₂CH₂CH(CH₃)₂ COOH H CH₃ CH₃ 3011 0 (CH₃)₂CHOC(O)— COCH₂CH₂CH(CH₃)₂ COOH H H H 3012 0 (CH₃)₂CHOC(O)— COCH₂CH₂CH(CH₃)₂ COOH H CH₃ CH₃ 3013 0 (CH₃)₂CHC(O)O— COCH₂CH₂CH(CH₃)₂ COOH H H H 3014 0 (CH₃)₂CHC(O)O— COCH₂CH₂CH(CH₃)₂ COOH H CH₃ CH₃ 3015 0 (CH₃)₂CHNHC(O)— COCH₂CH₂CH(CH₃)₂ COOH H H H 3016 0 (CH₃)₂CHNHC(O)— COCH₂CH₂CH(CH₃)₂ COOH H CH₃ CH₃

TABLE 70

No. n R^(1c) R^(1d) R² R³ R⁴ R⁵ R⁶ 3017 0 (CH₃)₂CH H COC₆H₅ COOH H H H 3018 0 (CH₃)₂CH H COC₆H₅ COOH H CH₃ CH₃ 3019 0 (CH₃)₂CHCH₂ H COC₆H₅ COOH H H H 3020 0 (CH₃)₂CHCH₂ H COC₆H₅ COOH H CH₃ CH₃ 3021 0 (CH₃)₂CHCH₂CH₂ H COC₆H₅ COOH H H H 3022 0 (CH₃)₂CHCH₂CH₂ H COC₆H₅ COOH H CH₃ CH₃ 3023 0 CH₃CH₂CH₂ H COC₆H₅ COOH H H H 3024 0 CH₃CH₂CH₂ H COC₆H₅ COOH H CH₃ CH₃ 3025 0 (CH₃)₂CH H COCH₂CH₂CH(CH₃)₂ COOH H H H 3026 0 (CH₃)₂CH H COCH₂CH₂CH(CH₃)₂ COOH H CH₃ CH₃ 3027 0 (CH₃)₂CHCH₂ H COCH₂CH₂CH(CH₃)₂ COOH H H H 3028 0 (CH₃)₂CHCH₂ H COCH₂CH₂CH(CH₃)₂ COOH H CH₃ CH₃ 3029 0 (CH₃)₂CHCH₂CH₂ H COCH₂CH₂CH(CH₃)₂ COOH H H H 3030 0 (CH₃)₂CHCH₂CH₂ H COCH₂CH₂CH(CH₃)₂ COOH H CH₃ CH₃ 3031 0 CH₃CH₂CH₂ H COCH₂CH₂CH(CH₃)₂ COOH H H H

TABLE 71 No. n R^(1c) R^(1d) R² R³ R⁴ R⁵ R⁶ 3032 0 CH₃CH₂CH₂ H COCH₂CH₂CH(CH₃)₂ COOH H CH₃ CH₃ 3033 0 (CH₃)₂CHCH₂ H COCH₂CH₂CH₂CH₃ COOH H H H 3034 0 (CH₃)₂CHCH₂ H COCH₂CH₂CH₂CH₃ COOH H CH₃ CH₃ 3035 0 (CH₃)₂CHCH₂ H COCH₂CH₂C₅H₉ COOH H H H 3036 0 (CH₃)₂CHCH₂ H COCH₂CH₂C₅H₉ COOH H CH₃ CH₃ 3037 1 (CH₃)₂CHCH₂ H COCH₂CH₂CH(CH₃)₂ COOH H H H 3038 1 (CH₃)₂CHCH₂ H COCH₂CH₂CH(CH₃)₂ COOH H CH₃ CH₃ 3039 2 (CH₃)₂CHCH₂ H COCH₂CH₂CH(CH₃)₂ COOH H H H 3040 2 (CH₃)₂CHCH₂ H COCH₂CH₂CH(CH₃)₂ COOH H CH₃ CH₃

TABLE 72

No. n R^(1h) R² R¹³ k 2001 0 4-CH₃CH(CH₃)C₆H₄CO— H OH 1 2002 0 4-CH₃CH(CH₃)C₆H₄CO— CH₃ OH 1 2003 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂CH₃ OH 1 2004 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂CH₂CH₃ OH 1 2005 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂CH₂CH₂CH₃ OH 1 2006 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂CH₂CH₂CH₂CH₃ OH 1 2007 0 4-CH₃CH(CH₃)C₆H₄CO— CH(CH₃)CH₃ OH 1 2008 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂CH(CH₃)CH₃ OH 1 2009 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂CH₂CH(CH₃)CH₃ OH 1 2010 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂CH₂CH₂CH(CH₃)CH₃ OH 1 2011 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂CH(CH₃)C₂H₅ OH 1 2012 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂CH₂CH (CH₃) C₂H₅ OH 1 2013 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂CH₂CH (C₂H₅) C₂H₅ OH 1 2014 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂F OH 1 2015 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂OH OH 1 2016 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂CH₂OH OH 1

TABLE 73 No. n R^(1h) R² R¹³ k 2017 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂CH₂CH₂OH OH 1 2018 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂CH₂CH₂CH₂OH OH 1 2019 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂CH₂CH₂CH₂CH₂OH OH 1 2020 0 4-CH₃CH(CH₃)C₆H₄CO— CH(OH)CH₂OH OH 1 2021 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂CH(OH)CH₂OH OH 1 2022 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂CH(OH)CH₂CH₂OH OH 1 2023 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂CH₂CH(OH)CH₂CH₂OH OH 1 2024 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂OC(O)NH₂ OH 1 2025 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂OC(O)CH₃ OH 1 2026 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂OC(O)CH₂C₆H₅ OH 1 2027 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂COOH OH 1 2028 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂CH₂COOH OH 1 2029 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂CH₂CH₂COOH OH 1 2030 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂CH₂CH₂CH₂COOH OH 2031 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂CH₂CH₂CH₂CH₂COOH OH 1 2032 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂COOCH₃ OH 2033 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂COOC₂H₅ OH 1 2034 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂COO-n-C₃H₇ OH 1 2035 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂COO-i-C₃H₇ OH 1 2036 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂COOC₆H₅ OH 1 2037 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂COOCH₂C₆H₅ OH 1 2038 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂CONH₂ OH 1

TABLE 74 No. n R^(1h) R² R¹³ k 2039 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂CONHOH OH 1 2040 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂CONHCH₃ OH 1 2041 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂CONHC₂H₅ OH 1 2042 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂CONH-n-C₃H₇ OH 1 2043 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂CONH-i-C₃H₇ OH 1 2044 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂CON(CH₃)₂ OH 1 2045 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂CON(n-C₃H₇)₂ OH 1 2046 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂CON(C₂H₅)₂ OH 1 2047 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂CONHC₆H₅ OH 1 2048 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂CH₂COOCH₃ OH 1 2049 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂CH₂COOCH₂C₆H₅ OH 1 2050 0 4-CH₃CH(CH₃)C₆H₄CO— CH(CH₃)COOH OH 1 2051 0 4-CH₃CH(CH₃)C₆H₄CO— CH(CH₂OH)COOH OH 1 2052 0 4-CH₃CH(CH₃)C₆H₄CO— CH(CH₂COOH)COOH OH 1 2053 0 4-CH₃CH(CH₃)C₆H₄CO— CH(CH₂CONH₂)COOH OH 1 2054 0 4-CH₃CH(CH₃)C₆H₄CO— CH(CH₂CH₂COOH)COOH OH 1 2055 0 4-CH₃CH(CH₃)C₆H₄CO— CH(CH₂CH₂CONH₂)COOH OH 1 2056 0 4-CH₃CH(CH₃)C₆H₄CO— CH(4-Imidazolylmethyl)COOH OH 1 2057 0 4-CH₃CH(CH₃)C₆H₄CO— CH(CH(C₂H₅)CH₃)COOH OH 1 2058 0 4-CH₃CH(CH₃)C₆H₄CO— CH(CH₂CH(CH₃)CH₃)COOH OH 1 2059 0 4-CH₃CH(CH₃)C₆H₄CO— CH(CH₂CH₂SCH₃)COOH OH 1 2060 0 4-CH₃CH(CH₃)C₆H₄CO— CH(CH(OH)CH₃)COOH OH 1

TABLE 75 No. n R^(1h) R² R¹³ k 2061 0 4-CH₃CH(CH₃)C₆H₄CO— CH(CH₂-(4-HO)C₆H₅)COOH OH 1 2062 0 4-CH₃CH(CH₃)C₆H₄CO— CH(CH₂C₆H₅)COOH OH 1 2063 0 4-CH₃CH(CH₃)C₆H₄C0— CH(3-Indolylmethyl)COOH OH 1 2064 0 4-CH₃CH(CH₃)C₆H₄CO— CH(i-C₃H₇)COOH OH 1 2065 0 4-CH₃CH(CH₃)C₆H₄C0— CH₂CN OH 1 2066 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂NO₂ OH 1 2067 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂COCH₃ OH 1 2068 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂C(OCH₃)₂CH₃ OH 1 2069 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂C(SCH₃)₂CH₃ OH 1 2070 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂CH₂SH OH 1 2071 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂C(NOH)CH₃ OH 1 2072 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂SH OH 1 2073 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂SO₃H OH 1 2074 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂S(O)₂CH₃ OH 1 2075 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂S(O)CH₃ OH 1 2076 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂S(O)₂NH₂ OH 1 2077 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂OCH₃ OH 1 2078 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂CH₂OCH₃ OH 1 2079 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂CH₂CH₂OCH₃ OH 1 2080 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂SCH₃ OH 1 2081 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂CH₂SCH₃ OH 1 2082 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂CH₂CH₂SCH₃ OH 1

TABLE 76 No. n R^(1h) R² R¹³ k 2083 0 4-CH₃CH(CH₃)C₆H₄CO— CHCH₂ OH 1 2084 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂CHCH₂ OH 1 2085 0 4-CH₃CH(CH₃)C₆H₄CO— Cyclopropyl OH 1 2086 0 4-CH₃CH(CH₃)C₆H₄CO— Cyclobutyl OH 1 2087 0 4-CH₃CH(CH₃)C₆H₄CO— Cyclopentyl OH 1 2088 0 4-CH₃CH(CH₃)C₆H₄CO— Cyclohexyl OH 1 2089 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂C₆H₅ OH 1 2090 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂CH₂C₆H₅ OH 1 2091 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂C₆H₁₁ OH 1 2092 0 4-CH₃CH(CH₃)C₆H₄CO— CH(CH₃)C₆H₅ OH 1 2093 0 4-CH₃CH(CH₃)C₆H₄CO— 2-Thienylmethyl OH 1 2094 0 4-CH₃CH(CH₃)C₆H₄CO— 2-Furfuryl OH 1 2095 0 4-CH₃CH(CH₃)C₆H₄Cd— 2-Pyranylmethyl OH 1 2096 0 4-CH₃CH(CH₃)C₆H₄CO— 1-Isobenzofuryl- OH 1 methyl 2097 0 4-CH₃CH(CH₃)C₆H₄CO— 2-Pyrrolylmethyl OH 1 2098 0 4-CH₃CH(CH₃)C₆H₄CO— 1-Imidazolylmethyl OH 1 2099 0 4-CH₃CH(CH₃)C₆H₄CO— 1-Pyrazolylmethyl OH 1 2100 0 4-CH₃CH(CH₃)C₆H₄CO— 3-Isothiazolylmethyl OH 1 2101 0 4-CH₃CH(CH₃)C₆H₄CO— 3-Isoxazolylmethyl OH 1 2102 0 4-CH₃CH(CH₃)C₆H₄CO— 2-Pyridylmethyl OH 1 2103 0 4-CH₃CH(CH₃)C₆H₄CO— 2-Pyrazinylmethyl OH 1 2104 0 4-CH₃CH(CH₃)C₆H₄CO— 2-Pyrimidinylmethyl OH 1

TABLE 77 No. n R^(1h) R² R¹³ k 2105 0 4-CH₃CH(CH₃)C₆H₄CO— 3-Pyridazinylmethyl OH 1 2106 0 4-CH₃CH(CH₃)C₆H₄CO— 1-Isoindolylmethyl OH 1 2107 0 4-CH₃CH(CH₃)C₆H₄CO— 2-Indolylmethyl OH 1 2108 0 4-CH₃CH(CH₃)C₆H₄CO— 3-(1H-Indazolyl)- OH 1 methyl 2109 0 4-CH₃CH(CH₃)C₆H₄CO— 2-Purinylmethyl OH 1 2110 0 4-CH₃CH(CH₃)C₆H₄CO— 1-Isoquinolylmethyl OH 1 2111 0 4-CH₃CH(CH₃)C₆H₄CO— 2-Quinolylmethyl OH 1 2112 0 4-CH₃CH(CH₃)C₆H₄CO— 1-Phthalazinyl OH 1 methyl 2113 0 4-CH₃CH(CH₃)C₆H₄CO— 2-Napthylidinyl- OH 1 methyl 2114 0 4-CH₃CH(CH₃)C₆H₄CO— 2-Quinoxalinyl- OH 1 methyl 2115 0 4-CH₃CH(CH₃)C₆H₄CO— 2-Quinazolinyl- OH 1 methyl 2116 0 4-CH₃CH(CH₃)C₆H₄CO— 3-Cinnolinylmethyl OH 1 2117 0 4-CH₃CH(CH₃)C₆H₄CO— 2-Oxazolylmethyl OH 1 2118 0 4-CH₃CH(CH₃)C₆H₄CO— 2-Thiazolylmethyl OH 1 2119 0 4-CH₃CH(CH₃)C₆H₄CO— 2-Benzo[b]- OH 1 furylmethyl 2120 0 4-CH₃CH(CH₃)C₆H₄CO— 2-Benzo[b]- OH 1 thienylmethyl 2121 0 4-CH₃CH(CH₃)C₆H₄CO— 3-(1,2,4-Triazinyl)- OH 1 methyl 2122 0 4-CH₃CH(CH₃)C₆H₄CO— 2-Benz[d]- OH 1 imidazolylmethyl 2123 0 4-CH₃CH(CH₃)C₆H₄CO— 2-Benz[d]- OH 1 oxazolylmethyl 2124 0 4-CH₃CH(CH₃)C₆H₄CO— Phenyl OH 1 2125 0 4-CH₃CH(CH₃)C₆H₄CO— 2-Naphthyl OH 1 2126 0 4-CH₃CH(CH₃)C₆H₄CO— 2-Thiazolyl OH 1

TABLE 78 No. n R^(1h) R² R¹³ k 2127 0 4-CH₃CH(CH₃)C₆H₄CO— 4-Imidazolyl OH 1 2128 0 4-CH₃CH(CH₃)C₆H₄CO— 3-Pyrazolyl OH 1 2129 0 4-CH₃CH(CH₃)C₆H₄CO— 3-Isoxazolyl OH 1 2130 0 4-CH₃CH(CH₃)C₆H₄CO— 5-Isothiazolyl OH 1 2131 0 4-CH₃CH(CH₃)C₆H₄CO— 2-Pyrimidinyl OH 1 2132 0 4-CH₃CH(CH₃)C₆H₄CO— 3-(1,2,4-Triazolyl) OH 1 2133 0 4-CH₃CH(CH₃)C₆H₄CO— 2-Pyridyl OH 1 2134 0 4-CH₃CH(CH₃)C₆H₄CO— 2-Benzoxazolyl OH 1 2135 0 4-CH₃CH(CH₃)C₆H₄CO— 3-Benzothienyl OH 1 2136 0 4-CH₃CH(CH₃)C₆H₄CO— 2-Benzofuryl OH 1 2137 0 4-CH₃CH(CH₃)C₆H₄CO— 5-Indolyl OH 1 2138 0 4-CH₃CH(CH₃)C₆H₄CO— 2-Pyrazinyl OH 1 2139 0 4-CH₃CH(CH₃)C₆H₄CO— 3-Quinolyl OH 1 2140 0 4-CH₃CH(CH₃)C₆H₄CO— 5-Tetrazolyl OH 1 2141 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂CONHCH₂C₆H₅ OH 1 2142 0 FCH₂ CH₂CH₂COOCH₂C₆H₅ OH 1 2143 0 HOCH₂ CH₂CH₂COOCH₂C₆H₅ OH 1 2144 0 HOCH₂CH₂ CH₂CH₂COOCH₂C₆H₅ OH 1 2145 0 HOCH₂CH₂CH₂ CH₂CH₂COOCH₂C₆H₅ OH 1 2146 0 HOCH₂CH₂CH₂CH₂ CH₂CH₂COOCH₂C₆H₅ OH 1 2147 0 HOCH₂CH₂CH₂CH₂CH₂ CH₂CH₂COOCH₂C₆H₅ OH 1 2148 0 HOCH₂CH(OH)CH₂ CH₂CH₂COOCH₂C₆H₅ OH 1

TABLE 79 No. n R^(1h) R² R¹³ k 2149 0 HOCH₂CH₂CH(OH)-CH₂ CH₂CH₂COOCH₂C₆H₅ OH 1 2150 0 HOCH₂CH(OH)CH₂CH₂CH₂ CH₂CH₂COOCH₂C₆H₅ OH 1 2151 0 H₂NC(O)OCH₂ CH₂CH₂COOCH₂C₆H₅ OH 1 2152 0 CH₃C(O)OCH₂ CH₂CH₂COOCH₂C₆H₅ OH 1 2153 0 HOOCCH₂ CH₂CH₂COOCH₂C₆H₅ OH 1 2154 0 HOOCCH₂CH₂ CH₂CH₂COOCH₂C₆H₅ OH 1 2155 0 HOOCCH₂CH₂CH₂ CH₂CH₂COOCH₂C₆H₅ OH 1 2156 0 HOOCCH₂CH₂CH₂CH₂ CH₂CH₂COOCH₂C₆H₅ OH 1 2157 0 HOOCCH₂CH₂CH₂CH₂CH₂ CH₂CH₂COOCH₂C₆H₅ OH 1 2158 0 CH₃OC(O)CH₂ CH₂CH₂COOCH₂C₆H₅ OH 1 2159 0 C₆H₅CH₂OC(O)CH₂ CH₂CH₂COOCH₂C₆H₅ OH 1 2160 0 n-C₃H₇OC(O)CH₂ CH₂CH₂COOCH₂C₆H₅ OH 1 2161 0 i-C₃H₇OC(O)CH₂ CH₂CH₂COOCH₂C₆H₅ OH 1 2162 0 C₆H₅OC(O)CH₂ CH₂CH₂COOCH₂C₆H₅ OH 1 2163 0 H₂NC(O)CH₂ CH₂CH₂COOCH₂C₆H₅ OH 1 2164 0 HONHC(O)CH₂ CH₂CH₂COOCH₂C₆H₅ OH 1 2165 0 CH₃NHC(O)CH₂ CH₂CH₂COOCH₂C₆H₅ OH 1 2166 0 C₂H₅NHC(O)CH₂ CH₂CH₂COOCH₂C₆H₅ OH 1 2167 0 n-C₃H₇NHC(O)CH₂ CH₂CH₂COOCH₂C₆H₅ OH 1 2168 0 CH₃OC(O)CH₂CH₂ CH₂CH₂COOCH₂C₆H₅ OH 1 2169 0 C₆H₅OC(O)CH₂CH₂ CH₂CH₂COOCH₂C₆H₅ OH 1 2170 0 H₂N CH₂CH₂COOCH₂C₆H₅ OH 1

TABLE 80 No. n R^(1h) R² R¹³ k 2171 0 NCCH₂ CH₂CH₂COOCH₂C₆H₅ OH 1 2172 0 CH₃COCH₂ CH₂CH₂COOCH₂C₆H₅ OH 1 2173 0 CH₃C(OCH₃)₂CH₂ CH₂CH₂COOCH₂C₆H₅ OH 1 2174 0 CH₃C(SCH₃)₂CH₂ CH₂CH₂COOCH₂C₆H₅ OH 1 2175 0 CH₃C(NOH)CH₂ CH₂CH₂COOCH₂C₆H₅ OH 1 2176 0 NSCH₂ CH₂CH₂COOCH₂C₆H₅ OH 1 2177 0 CH₃S(O)₂CH₂ CH₂CH₂COOCH₂C₆H₅ OH 1 2178 0 H₂NS(O)₂CH₂ CH₂CH₂COOCH₂C₆H₅ OH 1 2179 0 CH₃CH₂S(O)₂CH₂ CH₂CH₂COOCH₂C₆H₅ OH 1 2180 0 CH₃OCH₂ CH₂CH₂COOCH₂C₆H₅ OH 1 2181 0 CH₃OCH₂CH₂ CH₂CH₂COOCH₂C₆H₅ OH 1 2182 0 CH₃OCH₂CH₂CH₂ CH₂CH₂COOCH₂C₆H₅ OH 1 2183 0 CH₃SCH₂ CH₂CH₂COOCH₂C₆H₅ OH 1 2184 0 CH₃SCH₂CH₂ CH₂CH₂COOCH₂C₆H₅ OH 1 2185 0 CH₃SCH₂CH₂CH₂ CH₂CH₂COOCH₂C₆H₅ OH 1 2186 0 C₆H₅CH₂ CH₂CH₂COOCH₂C₆H₅ OH 1 2187 0 C₆H₅CH₂CH₂ CH₂CH₂COOCH₂C₆H₅ OH 1 2188 0 C₆H₁₁CH₂ CH₂CH₂COOCH₂C₆H₅ OH 1 2189 0 2-Thienylmethyl CH₂CH₂COOCH₂C₆H₅ OH 1 2190 0 2-Furfuryl CH₂CH₂COOCH₂C₆H₅ OH 1 2191 0 2-Pyranylmethyl CH₂CH₂COOCH₂C₆H₅ OH 1 2192 0 1-Isobenzofurylmethyl CH₂CH₂COOCH₂C₆H₅ OH 1

TABLE 81 No. n R^(1h) R² R¹³ k 2193 0 2-Pyrrolylmethyl CH₂CH₂COOCH₂C₆H₅ OH 1 2194 0 1-Imidazolylmethyl CH₂CH₂COOCH₂C₆H₅ OH 1 2195 0 1-Pyrazolylmethyl CH₂CH₂COOCH₂C₆H₅ OH 1 2196 0 3-Isothiazolylmethyl CH₂CH₂COOCH₂C₆H₅ OH 1 2197 0 3-Isoxazolylmethyl CH₂CH₂COOCH₂C₆H₅ OH 1 2198 0 2-Pyridylmethyl CH₂CH₂COOCH₂C₆H₅ OH 1 2199 0 2-Pyrazinylmethyl CH₂CH₂COOCH₂C₆H₅ OH 1 2200 0 2-Pyrimidinylmethyl CH₂CH₂COOCH₂C₆H₅ OH 1 2201 0 3-Pyridazinylmethyl CH₂CH₂COOCH₂C₆H₅ OH 1 2202 0 1-Isoindolyl- CH₂CH₂COOCH₂C₆H₅ OH 1 methyl 2203 0 2-Indolylmethyl CH₂CH₂COOCH₂C₆H₅ OH 1 2204 0 3-(1H-Indazolyl)- CH₂CH₂COOCH₂C₆H₅ OH 1 methyl 2205 0 2-Purinylmethyl CH₂CH₂COOCH₂C₆H₅ OH 1 2206 0 1-Isoquinolylmethyl CH₂CH₂COOCH₂C₆H₅ OH 1 2207 0 2-Quinolylmethyl CH₂CH₂COOCH₂C₆H₅ OH 1 2208 0 1-Phthalazinylmethyl CH₂CH₂COOCH₂C₆H₅ OH 1 2209 0 2-Naphthylidinyl- CH₂CH₂COOCH₂C₆H₅ OH 1 methyl 2210 0 2-Quinoxalinylmethyl CH₂CH₂COOCH₂C₆H₅ OH 1 2211 0 2-Quinazolinylmethyl CH₂CH₂COOCH₂C₆H₅ OH 1 2212 0 3-Cinnolinylmethyl CH₂CH₂COOCH₂C₆H₅ OH 1 2213 0 2-Oxazolylmethyl CH₂CH₂COOCH₂C₆H₅ OH 1 2214 0 2-Thiazolylmethyl CH₂CH₂COOCH₂C₆H₅ OH 1

TABLE 82 No. n R^(1h) R² R¹³ k 2215 0 2-Benzo[b]furylmethyl CH₂CH₂COOCH₂C₆H₅ OH 1 2216 0 2-Benzo[b]thienylmethyl CH₂CH₂COOCH₂C₆H₅ OH 1 2217 0 3-(1,2,4-triazinyl)methyl CH₂CH₂COOCH₂C₆H₅ OH 1 2218 0 2-Benz[d]imidazolylmethyl CH₂CH₂COOCH₂C₆H₅ OH 1 2219 0 2-Benz[d]oxazolylmethyl CH₂CH₂COOCH₂C₆H₅ OH 1 2220 0 C₆H₅CO CH₂CH₂COOCH₂C₆H₅ OH 1 2221 0 CH₃CO CH₂CH₂COOCH₂C₆H₅ OH 1 2222 0 CH₃CH₂CO CH₂CH₂CO9CH₂C₆H₅ OH 1 2223 0 CH₃CH₂CH₂CO CH₂CH₂COOCH₂C₆H₅ OH 1 2224 0 CH₃CH₂CH₂CH₂CO CH₂CH₂COOCH₂C₆H₅ OH 1 2225 0 CH₃CH₂CH₂CH₂CH₂CO CH₂CH₂COOCH₂C₆H₅ OH 1 2226 0 CH₃CH(CH₃)CO CH₂CH₂COOCH₂C₆H₅ OH 1 2227 0 CH₃CH₂CH(CH₃)CO CH₂CH₂COOCH₂C₆H₅ OH 1 2228 0 C₆H₅CH₂CO CH₂CH₂COOCH₂C₆H₅ OH 1 2229 0 H₂NCH(CH₂OH)CO CH₂CH₂COOCH₂C₆H₅ OH 1 2230 0 H₂NCH(CH₂COOH)CO CH₂CH₂COOCH₂C₆H₅ OH 1 2231 0 H₂NCH(CH₂CONH₂)CO CH₂CH₂COOCH₂C₆H₅ OH 1 2232 0 H₂NCH(CH₂CH₂COOH)CO CH₂CH₂COOCH₂C₆H₅ OH 1 2233 0 H₂NCH(CH₂CH₂CONH₂)CO CH₂CH₂COOCH₂C₆H₅ OH 1 2234 0 H₂NCH(4-imidazolylmethyl)CO CH₂CH₂COOCH₂C₆H₅ OH 1 2235 0 H₂NCH(CH(C₂H₅)CH₃)CO CH₂CH₂COOCH₂C₆H₅ OH 1 2236 0 H₂NCH(CH₂CH(CH₃)CH₃)CO CH₂CH₂COOCH₂C₆H₅ OH 1

TABLE 83 No. n R^(1n) R² R¹³ k 2237 0 H₂NCH(CH₂CH₂SCH₃)CO CH₂CH₂COOCH₂C₆H₅ OH 1 2238 0 H₂NCH(CH(OH)CH₃)CO CH₂CH₂COOCH₂C₆H₅ OH 1 2239 0 H₂NCH(CH₂-(4-HO)C₆H₅)CO CH₂CH₂COOCH₂C₆H₅ OH 1 2240 0 H₂NCH(CH₂C₆H₅)CO CH₂CH₂COOCH₂C₆H₅ OH 1 2241 0 H₂NCH(3-indolylmethyl)CO CH₂CH₂COOCH₂C₆H₅ OH 1 2242 0 2-Thienylmethylcarbonyl CH₂CH₂COOCH₂C₆H₅ OH 1 2243 0 2-Furfurylcarbonyl CH₂CH₂COOCH₂C₆H₅ OH 1 2244 0 2-Pyridylmethylcarbonyl CH₂CH₂COOCH₂C₆H₅ OH 1 2245 0 2-Quinolylmethylcarbonyl CH₂CH₂COOCH₂C₆H₅ OH 1 2246 0 2-Benzothienylmethylcarbonyl CH₂CH₂COOCH₂C₆H₅ OH 1 2247 0 2-Naphthylidinylmethylcarbonyl CH₂CH₂COOCH₂C₆H₅ OH 1 2248 0 2-Thiazolylmethylcarbonyl CH₂CH₂COOCH₂C₆H₅ OH 1 2249 0 2-Pyrimidinylmethylcarbonyl CH₂CH₂COOCH₂C₆H₅ OH 1 2250 0 2-Benzoxazolylmethylcarbonyl CH₂CH₂COOCH₂C₆H₅ OH 1 2251 0 2-Indolylmethylcarbonyl CH₂CH₂COOCH₂C₆H₅ OH 1 2252 0 2-Thiazolylcarbonyl CH₂CH₂COOCH₂C₆H₅ OH 1 2253 0 2-Pyrimidinylcarbonyl CH₂CH₂COOCH₂C₆H₅ OH 1 2254 0 2-Indolylcarbonyl CH₂CH₂COOCH₂C₆H₅ OH 1 2255 0 2-Benzothienylcarbonyl CH₂CH₂COOCH₂C₆H₅ OH 1 2256 0 5-Quinolylcarbonyl CH₂CH₂COOCH₂C₆H₅ OH 1 2257 0 4-CH₃CH(CH₃)C₆H₄CO— S(O)₂CH₃ OH 1 2258 0 4-CH₃CH(CH₃)C₆H₄CO— S(O)₂C₆H₅ OH 1

TABLE 84 No. n R^(1h) R² R¹³ k 2259 0 4-CH₃CH(CH₃)C₆H₄SO₂— CH₂CH₂COOCH₂C₆H₅ OH 1 2260 0 4-CH₃CH(CH₃)C₆H₄SO₂— S(O)₂CH₃ OH 1 2261 0 4-CH₃CH(CH₃)C₆H₄SO₂— S(O)₂C₆H₅ OH 1 2262 0 4-CH₃CH(CH₃)C₆H₄SO₂— H OH 2 2263 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂CH₂OH OH 2 2264 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂OCONH₂ OH 2 2265 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂OCOCH₃ OH 2 2266 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂COOH OH 2 2267 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂CONH₂ OH 2 2268 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂CH₂C₆H₅ OH 3 2269 1 4-CH₃CH(CH₃)C₆H₄CO— H OH 1 2270 1 4-CH₃CH(CH₃)C₆H₄CO— CH₂CH₂OH OH 1 2271 1 4-CH₃CH(CH₃)C₆H₄CO— CH₂OCONH₂ OH 1 2272 1 4-CH₃CH(CH₃)C₆H₄CO— CH₂OC(O)CH₃ OH 1 2273 1 4-CH₃CH(CH₃)C₆H₄CO— CH₂COOH OH 1 2274 1 4-CH₃CH(CH₃)C₆H₄CO— CH₂CONH₂ OH 1 2275 1 4-CH₃CH(CH₃)C₆H₄CO— CH₂S(O)₂CH₃ OH 1 2276 2 4-CH₃CH(CH₃)C₆H₄CO— H OH 1 2277 2 4-CH₃CH(CH₃)C₆H₄CO— CH₂CH₂OH OH 1 2278 2 4-CH₃CH(CH₃)C₆H₄CO— CH₂OCONH₂ OH 1 2279 2 4-CH₃CH(CH₃)C₆H₄CO— CH₂OC(O)CH₃ OH 1 2280 2 4-CH₃CH(CH₃)C₆H₄CO— CH₂COOH OH 1

TABLE 85 No. n R^(1h) R² R¹³ k 2281 2 4-CH₃CH(CH₃)C₆H₄CO— CH₂CONH₂ OH 1 2282 2 4-CH₃CH(CH₃)C₆H₄CO— CH₂S(O)₂CH₃ OH 1 2283 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂CH₂C₆H₅ H 1 2284 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂CH₂C₆H₅ Cl 1 2285 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂CH₂C₆H₅ OCH₃ 1 2286 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂CH₂C₆H₅ OC₂H₅ 1 2287 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂CH₂C₆H₅ OC₆H₅ 1 2288 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂CH₂C₆H₅ OCH₂C₆H₅ 1 2289 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂CH₂C₆H₅ SCH₃ 1 2290 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂CH₂C₆H₅ NH₂ 1 2291 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂CH₂C₆H₅ NHOH 1 2292 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂CH₂C₆H₅ NHCH₃ 1 2293 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂CH₂C₆H₅ N(CH₃)₂ 1 2294 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂CH₂C₆H₅ NHCH₂C₆H₅ 1 2295 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂CH₂C₆H₅ NHC₆H₅ 1 2296 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂CH₂C₆H₅ CH₃ 1 2297 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂CH₂C₆H₅ C₂H₅ 1 2298 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂CH₂C₆H₅ C₆H₅ 1 2299 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂CH₂C₆H₅ CH₂C₆H₅ 1 2300 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂CH₂C₆H₅ 2-Thienyl 1 2301 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂CH₂C₆H₅ NHCH(CH₃)COOH 1 2302 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂CH₂C₆H₅ NHCH(CH₃)CONH₂ 1 2303 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂CH₂C₆H₅ NHCH(CH₂COOH)COOH 1 2304 0 4-CH₃CH(CH₃)C₆H₄CO— CH₂CH₂C₆H₅ NHCH(CH₂C₆H₅)COOH 1

TABLE 86 No. n R^(1h) R² R¹³ k 2305 0 4-CH₃CH(CH₃)C₆H₄CO- CH₂CH₂C₆H₅ Leu-Leu-OH 1 2306 0 4-CH₃CH(CH₃)C₆H₄CO- CH₂CH₂C₆H₅ Leu-Ala- 1 Leu-OH 2307 0 OHC- CH₂CH₂C₆H₅ OH 1 2308 0 HOCH₂- CH₂CH₂C₆H₅ OH 1 2309 0 H₂N- CH₂CH₂C₆H₅ OH 1 2310 0 ClS(O)₂- CH₂CH₂C₆H₅ OH 1 2311 0 NCCO- CH₂CH₂C₆H₅ OH 1 2312 0 HOC(O)C(O) - CH₂CH₂C₆H₅ OH 1 2313 0 H₃COC(O)NH- CH₂CH₂C₆H₅ OH 1 2314 0 HOC(O)- CH₂CH₂C₆H₅ OH 1 2315 0 CH₃NH- CH₂CH₂C₆H₅ OH 1 2316 0 CH₃CO- CH₂CH₂C₆H₅ OH 1 2317 0 CH₂CHNH- CH₂CH₂C₆H₅ OH 1 2318 0 CH₂CHCO- CH₂CH₂C₆H₅ OH 1 2319 0 CH₂CHCH₂- CH₂CH₂C₆H₅ OH 1 2320 0 CH₂CHS(O)₂ CH₂CH₂C₆H₅ OH 1 2321 0 C₆H₁₁NH- CH₂CH₂C₆H₅ OH 1 2322 0 C₆H₁₁S(O)₂ CH₂CH₂C₆H₅ OH 1 2323 0 H₂NCO- CH₂CH₂C₆H₅ OH 1 2324 0 CH₃OC(O)- CH₂CH₂C₆H₅ OH 1 2325 0 H-Leu-Leu- CH₂CH₂ OH 1 COOCH₂C₆H₅ 2326 0 H-Leu-Ala-Leu- CH₂CH₂ OH 1 COOCH₂C₆H₅

Some of the compounds of the present invention represented by general formula [1] or salts thereof have isomers such as optical isomers, geometrical isomers and tautomers. In such cases, the present invention involves such isomers. Further, the present invention involves solvated products, hydrated products and a variety of crystal forms.

Next, the process for producing the compounds of the present invention will be described.

The compounds of the present invention can be synthesized according to, for example, the Production Processes 1 and 2 mentioned below.

[Production Process 1]

[Production Process 2]

wherein R², R³, R⁴, R⁵, R⁶ and A are as defined above; R^(2a) represents an unsubstituted or substituted acyl or sulfonyl group; R′ represents an unsubstituted or substituted alkyl or aryl group; R″ represents tert-butyl group or trichloroethyl group; R⁸ and R⁹, same or different, each represents hydrogen atom or an unsubstituted or substituted alkyl, aryl or heterocyclic group; R¹⁰ represents an unsubstituted or substituted amino group, n′ represents 1 or 2; and Z represents halogen atom, alkylsulfonyloxy group or arylsulfonyloxy group.

[Production Process 1]

Next, the process for producing the compounds of the present invention will be described.

The compounds of the present invention can be produced by combining the processes which are known in themselves, namely, according to the production processes mentioned below, for example.

The compound of the general formula [1a] can be produced by, for example, the process mentioned in Yakugaku Zasshi, Vol. 91, No, 3, Pages 363-383 (1971), or the like. More concretely speaking, the compounds of the present invention can be obtained by reacting a compound of general formula [2] with an amine represented by general formula [3] or an ammonium salt and a compound represented by general formula [4] in the presence or absence of a dehydrating agent and/or a catalyst, and subjecting the reaction product to a dehydrating ring closure.

As the amines which can be used in this reaction, primary amines such as methylamine, benzylamine, aniline, phenethylamine or the like and amino acids such as leucine, asparagine, aspartic acid, β-alanine or the like can be referred to. As the ammonium salts, ammonium carbonate, ammonium sulfate and the like can be referred to. The amine of general formula [3] or the ammonium salt is used in an amount of 1-10 mol and preferably 1-2 mol per mol of the compound of general formula [2]. The compound of general formula [4] is used in an amount of 1-10 mol and preferably 1-2 mol per mol of the compound of general formula [2]. As the dehydrating agent which can be used according to the need, zeolam, molecular sieve, calcium chloride, magnesium sulfate, diphosphorus pentoxide and the like can be referred to, and the amount thereof is 1-10 times (w/w) and preferably 1-2 times (w/w) as much as the weight of the compound of general formula [2]. As the catalyst which can be used according to the need, paratoluenesulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid and the like can be referred to, and the amount thereof is 0.001-3 mol and preferably 0.01-0.1 mol per mol of the compound of general formula [2]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitriles such as acetonitrile and the like; alcohols such as methyl alcohol, ethyl alcohol, isopropyl alcohol and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. This reaction is carried out usually at 0-150° C. and preferably at 25-120° C. for a period of 30 minutes to 24 hours.

The compound of general formula [1b] can be obtained, for example, according to the process mentioned in Yakugaku Zasshi, Vol. 91, No. 3, Pages 363-383 (1971), or the like. More concretely speaking, it can be obtained by reacting a compound of general formula [2] with an amine represented by general formula [3] or an ammonium salt and a compound represented by general formula [5] which can be synthesized according to the method described in SYNTHETIC COMMUNICATIONS, Vol. 21, No. 2, Pages 249-263 (1991) or the like in the presence or absence of a dehydrating agent and/or a catalyst, and subjecting the reaction product to a dehydrating ring closure. As the amines which can be used in this reaction, primary amines such as methylamine, benzylamine, aniline, phenethylamine and the like, amino acids such as leucine, asparagine, aspartic acid, β-alanine and the like, etc. can be referred to. As the ammonium salts, ammonium carbonate, ammonium sulfate and the like can be referred to. The amine represented by general formula [3] or the ammonium salt is used in an amount of 1-10 mol and preferably 1-2 mol per mol of the compound of general formula [2]. The compound of general formula [5] is used in an amount of 1-10 mol and preferably 1-2 mol per mol of the compound of general formula [2]. As the dehydrating agent, for example, zeolam, molecular sieve, calcium chloride, magnesium sulfate, diphosphorus pentoxide and the like can be used in an amount of 1-10 times (w/w) and preferably 1-2 times (w/w) as much as the weight of the compound of general formula [2]. As the catalyst which may be used according to the need, paratoluenesulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid and the like can be referred to, and the amount thereof is 0.001-3 mol and preferably 0.01-0.1 mol per mol of the compound of general formula [2]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitriles such as acetonitrile and the like; alcohols such as methyl alcohol, ethyl alcohol, isopropyl alcohol and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. This reaction is carried out usually at 0-150° C. and preferably at 25-120° C. for a period of 30 minutes to 24 hours.

The compound of general formula [1c] can be obtained, for example, according to the process mentioned in Yakugaku Zasshi, Vol. 91, No. 3, Pages 363-383 (1971), or the like. More concretely speaking, it can be obtained by reacting a compound of general formula [2] with an amine represented by general formula [3] or an ammonium salt and mercaptoacetic acid in the presence or absence of a dehydrating agent and/or a catalyst, and subjecting the reaction product to a dehydrating ring closure. As the amines which can be used in this reaction, primary amines such as methylamine, benzylamine, aniline, phenethylamine and the like, amino acids such as leucine, asparagine, aspartic acid, β-alanine and the like, etc. can be referred to. As the ammonium salts, ammonium carbonate, ammonium sulfate and the like can be referred to. The amine represented by general formula [3] or the ammonium salt is used in an amount of 1-10 mol and preferably 1-2 mol per mol of the compound of general formula [2]. The mercaptoacetic acid is used in an amount of 1-10 mol and preferably 1-2 mol per mol of the compound of general formula [2]. As the dehydrating agent which may be used according to the need, for example, zeolam, molecular sieve, calcium chloride, magnesium sulfate, diphosphorus pentoxide and the like can be used in an amount of 1-10 times (w/w) and preferably 1-2 times (w/w) as much as the weight of the compound of general formula [2]. As the catalyst which may be used according to the need, paratoluenesulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid and the like can be referred to, and the amount thereof is 0.001-3 mol and preferably 0.01-0.1 mol per mol of the compound of general formula [2]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitrites such as acetonitrile and the like; alcohols such as methyl alcohol, ethyl alcohol, isopropyl alcohol and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. This reaction is carried out usually at 0-150° C. and preferably at 25-120° C. for a period of 30 minutes to 24 hours. If desired, this reaction may be carried out in an atmosphere of inert gas such as argon or nitrogen.

The compound of general formula [1b] can be obtained by, for example, reacting a compound of general formula [1c] with a compound of general formula [6] in the presence of a base. As the base used in this reaction, for example, there can be referred to organolithium compounds such as n-butyllithium, phenyllithium, lithium diisopropylamide and the like; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride and the like; alkali metal carbonates such as potassium carbonate, sodium carbonate and the like; alkali hydroxides such as sodium hydroxide, potassium hydroxide and the like; etc. The base is used in an amount of 1-5 mol per mol of the compound of general formula [1c]. The compound of general formula [6] is used in an amount of 1-10 mol and preferably 1-2 mol per mol of the compound of general formula [1c]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; nitriles such as acetonitrile and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. This reaction is carried out usually at −78° C. to 150° C. and preferably at −50° C. to 120° C., for a period of 30 minutes to 24 hours. If desired, the reaction may be carried out in an atmosphere of inert gas such as argon or nitrogen.

The compound of general formula [1d] can be obtained by reacting a compound of general formula [1c] with an aldehyde or a ketone represented by general formula [7] in the presence or absence of an acid or a base.

As the acid which may be used in this reaction according to the need, for example, paratoluenesulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid and the like can be referred to. The amount thereof is 1-10 mol per mol of the compound of general formula [1c]. As the base which may be used according to the need, for example, there can be referred to organolithium compounds such as n-butyllithium, phenyllithium, lithium diisopropylamide and the like; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride and the like; alkali metal carbonates such as potassium carbonate, sodium carbonate and the like; alkali hydroxides such as sodium hydroxide, potassium hydroxide and the like; etc. The base is used in an amount of 1-10 mol per mol of the compound of general formula [1c]. The compound of general formula [7] is used in an amount of 1-10 mol and preferably 1-2 mol per mol of the compound of general formula [1c]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; nitrites such as acetonitrile and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. This reaction is carried out usually at −78° C. to 150° C. and preferably at −50° C. to 120° C., for a period of 30 minutes to 24 hours.

The compound of general formula [1a] can be obtained by, for example, subjecting a compound of general formula [1b] to a de-esterification reaction in the presence or absence of an acid or a base. As the acid which may be used in this reaction according to the need, for example, hydrochloric acid, sulfuric acid, acetic acid, trifluoro-acetic acid, paratoluenesulfonic acid and the like can be referred to, and the amount thereof is 1-50 mol and preferably 10-30 mol per mol of the compound of general formula [1b]. As the base which may be used according to the need, for example, there can be referred to organolithium compounds such as n-butyllithium, phenyllithium, lithium diisopropylamide and the like; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride and the like; alkali metal carbonates such as potassium carbonate, sodium carbonate and the like; alkali hydroxides such as sodium hydroxide, potassium hydroxide and the like; etc. The base is used in an amount of 1-50 mol and preferably 10-30 mol per mol of the compound of general formula [1b].

The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; nitrites such as acetonitrile and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; acetic acid; water; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. This reaction is carried out usually at 0-150° C. and preferably at 25-120° C., for a period of 30 minutes to 24 hours.

The compound of general formula [1e] can be obtained by, for example, oxidizing a compound of general formula [1a]. As the oxidant which can be used in this reaction, for example, peracids such as peracetic acid, trifluoro-peracetic acid, perbenzoic acid, m-chloroperbenzoic acid and the like; hydrogen peroxide; chromic acid; potassium permanganate and the like can be referred to. The oxidant is used in an amount of 0.5-5 mol and preferably 1-3 mol per mol of the compound of general formula [1a]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; alcohols such as methanol, ethanol and the like; esters such as methyl acetate, ethyl acetate and the like; nitrites such as acetonitrile and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; water; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. This reaction is carried out usually at a temperature ranging from 0° C. to reflux temperature of the used solvent and preferably at 0-30° C., for a period of 30 minutes to 24 hours.

[Production Process 2]

The compound of general formula [1f] can be obtained by, for example, the process mentioned in JP-A 53-44574, or the like. More concretely speaking, it can be obtained by reacting a compound of general formula [2] with a compound of general formula [8] in the presence or absence of a base, a dehydrating agent and a catalyst, and subjecting the product to a dehydrating ring closure. Although the compound of general formula [8] used in this reaction is not particularly critical, D-cysteine, L-cysteine, D-penicillamine and L-penicillamine of which C-terminal may optionally be protected and salts thereof can be referred to, for example. The compound of general formula [8] is used in an amount of 0.5-10 mol and preferably 1-2 mol per mol of the compound of general formula [2]. As the base which may be used according to the need, for example, organic amines such as dimethylaminopyridine, triethylamine, pyridine and the like; alkali metal carbonates such as potassium carbonate, sodium carbonate and the like; etc. can be referred to, and the amount thereof is 0.5-10 mol and preferably 1-2 mol per mol of the compound of general formula [2]. As the dehydrating agent which may be used according to the need, zeolam, molecular sieve, calcium chloride, magnesium sulfate, diphosphorus pentoxide and the like can be referred to, and the amount thereof is 1-10 times (w/w) and preferably 1-2 (w/w) times as much as the amount of the compound of general formula [2]. As the catalyst which may be used according to the need, paratoluenesulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid and the like can be referred to, and the amount thereof is 0.001-1 mol and preferably 0.01-0.1 mol per mol of the compound of general formula [2]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitrites such as acetonitrile and the like; alcohols such as methyl alcohol, ethyl alcohol, isopropyl alcohol and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; water; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. This reaction is carried out usually at 0-150° C. and preferably at 20-120° C., for a period of 30 minutes to 24 hours.

The compound of general formula [1g] can be obtained by, for example, subjecting a compound of general formula [1] to an acylation reaction or a sulfonylation reaction in the presence or absence of a base. As the acylating agent which can be used in this reaction, for example, acetic anhydride, acetyl chloride, benzoyl chloride, pyrrolecarbonyl chloride, thiazolecarbonyl chloride and the like can be referred to. As the sulfonylating agent, methanesulfonyl chloride, benzenesulfonyl chloride and the like can be referred to. The amounts of said acylating agent and sulfonylating agent are 0.5-10 mol and preferably 1-3 mol per mol of the compound of general formula [1]. As the base which may be used according to the need, organic amines such as dimethylaminopyridine, triethylamine, pyridine and the like and alkali metal carbonates such as potassium carbonate, sodium carbonate and the like can be referred to, and the amount thereof is 0.5-10 mol and preferably 1-3 mol per mol of the compound of general formula [1f].

The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitriles such as acetonitrile and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. The reaction is carried out usually at −20° C. to 150° C. and preferably at 0-120° C., for a period of 30 minutes to 24 hours.

The compound of general formula [1h] can be obtained by, for example, oxidizing a compound of general formula [1g]. As the oxidant which can be used in this reaction, for example, peracids such as peracetic acid, trifluoro-peracetic acid, perbenzoic acid, m-chloroperbenzoic acid and the like, hydrogen peroxide, chromic acid, potassium permanganate and the like can be referred to. The oxidant is used in an amount of 0.5-5 mol and preferably 1-3 mol per mol of the compound of general formula [1g]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; alcohols such as methanol, ethanol and the like; esters such as methyl acetate, ethyl acetate and the like; nitrites such as acetonitrile and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; water; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. The reaction is carried out usually at a temperature ranging from 0° C. to the reflux temperature of the used solvent and preferably at 0-30° C., for a period of 30 minutes to 24 hours.

The compound of general formula [1i] can be obtained by, for example, subjecting a compound of general formula [1g] to an amidation reaction.

This reaction is a usual amidation reaction, which can be carried out by, for example, a method via an acid chloride, a method via an acid anhydride, a method using a base, a condensing agent and an additive, etc. In a case of using a base, a condensing agent and an additive, the amines which can be used in the reaction include primary amines such as methylamine, benzylamine, aniline, phenethylamine, aminothiazole and the like; secondary amines such as dimethylamine, diethylamine, di-n-propylamine and the like; cyclic amines such as piperidine, morpholine and the like; amino acids such as leucine, asparagine, aspartic acid, β-alanine, methionine and the like; and esters thereof. The amine is used in an amount of 0.5-10 mol and preferably 1-3 mol per mol of the compound of general formula [1g]. As the base which can be use in this reaction, organic amines such as dimethylaminopyridine, triethylamine, pyridine, N-methylmorphline and the like and alkali metal carbonates such as potassium carbonate, sodium carbonate and the like can be referred to, and the amount thereof is 0.5-10 mol and preferably 1-3 mol per mol of the compound of general formula [1g]. As the condensing agent, dicyclohexyl-carbodiimide, diisopropyl-carbodiimide, N-ethyl-N′-3-dimethylaminopropyl carbodiimide, diphenyl phosphoryl azide and the like can be referred to, and as the additive, 1-hydroxybenzotriazole, N-hydroxysuccinimide and the like can be referred to. The amounts of the condensing agent and the additive are both 0.5-10 mol and preferably 1-3 mol per mol of the compound of general formula [1g]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitriles such as acetonitrile and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. The reaction is carried out usually at a temperature of −20° C. to 150° C. and preferably at 0-120° C., for a period of 30 minutes to 24 hours.

The compound of [1j] can be obtained by, for example, oxidizing a compound of general formula [1i].

As the oxidant which can be used in this reaction, peracids such as peracetic acid, trifluoro-peracetic acid, perbenzoic acid, m-chloroperbenzoic acid and the like; hydrogen peroxide; chromic acid and potassium permanganate and the like can be referred to. The oxidant is used in an amount of 0.5-5 mol and preferably 1-3 mol per mol of the compound of general formula [1i]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; alcohols such as methanol, ethanol and the like; esters such as methyl acetate, ethyl acetate and the like; nitrites such as acetonitrile and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; water; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. The reaction is carried out usually at a temperature ranging from 0° C. to the reflux temperature of the used solvent and preferably at 0-30° C., for a period of 30 minutes to 24 hours.

Furthermore, it is also possible to synthesize the compounds of the present invention according to the Production Processes 1a and 2a described below.

[Production Process 1a]

wherein

A is as defined above; R′ represents an unsubstituted or substituted alkyl or aryl group; R″ represents tert-butyl group; R′″ represents an unprotected or protected amino, hydroxyamino, alkylamino, arylamino, acylamino, alkoxycarbonylamino, arylsulfonylamino, alkylsulfonylamino or a group of the following general formula:

—(E²)_(q′)—R^(13′)

wherein E² represents amino acid residue; and R^(13′) represents an unprotected or protected hydroxyl, amino, alkylamino, acylamino, alkoxycarbonylamino, arylsulfonylamino, alkylsulfonylamino, or an unsubstituted or substituted alkyl or alkoxy group; and q′ represents 1, 2 or 3; and r represents 0, 1 or 2.

The compound of general formula [1k] can be obtained by, for example, the process mentioned in Yakugaku Zasshi, Vol. 91, No. 3, Pages 363-383 (1971), or the like. More concretely speaking, it can be obtained by reacting a compound of general formula [2] with an amine represented by general formula [23] and mercaptosuccinic acid in the presence or absence of a dehydrating agent and/or a catalyst, and subjecting the product to a dehydrating ring closure.

As the amine which can be used in this reaction, glycine tert-butyl ester, β-alanine tert-butyl ester and the like can be referred to. The amine of general formula [23] is used in an amount of 1-10 mol and preferably 1-2 mol per mol of the compound of general formula [2]. The mercaptosuccinic acid is used in an amount of 1-10 mol and preferably 1-2 mol per mol of the compound of general formula [2]. As the dehydrating agent which may be used according to the need, for example, zeolam, molecular sieve, calcium chloride, magnesium sulfate, diphosphorus pentoxide and the like can be referred to, and the amount thereof is 1-10 times (w/w) and preferably 1-2 times (w/w) as much as the amount of the compound of general formula [2]. As the catalyst which may be used according to the need, paratoluenesulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid and the like can be referred to, and the amount thereof is 0.001-3 mol and preferably 0.01-0.1 mol per mol of the compound of general formula [2]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitriles such as acetonitrile and the like; alcohols such as methanol, ethanol, isopropyl alcohol and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. The reaction is carried out usually at 0-150° C. and preferably at 25-120° C., for a period of 30 minutes to 24 hours.

The compound of general formula [1l] can be obtained by subjecting a compound of general formula [1k] to an esterification reaction.

This reaction may be practiced according to the usual methods of esterification, such as the method via an acid chloride, the method via an acid anhydride, the method using a base and an alkyl halide, the method of using a condensing agent and an additive, etc. In the case of using a base and an alkyl halide, the base which can be used include organic amines such as dimethylaminopyridine, triethylamine, pyridine, N-methylmorpholine and the like; alkali metal carbonates such as potassium carbonate, sodium carbonate and the like; etc. The amount of the base is 0.5-10 mol and preferably 1-3 mol per mol of the compound of general formula [1k]. As the alkyl halide which can be used in this reaction, methyl iodide, ethyl iodide, benzyl bromide and the like can be referred to, and the amount thereof is 0.5-10 mol and preferably 1-3 mol per mol of the compound of general formula [1k]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitriles such as acetonitrile and the like; amides such as N,N-dimethylformamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; and sulfoxides such as dimethyl sulfoxide and the like. The reaction is carried out usually at 0-200° C. and preferably at 25-150° C., for a period of 10 minutes to 24 hours. In the case of using a condensing agent and an additive, the objective compound can be obtained by subjecting an alcohol such as ethanol, benzyl alcohol or the like to a condensation reaction with a condensing agent and an additive. As the condensing agent used in this reaction, for example, dicyclohexyl carbodiimide, diisopropyl carbodiimide, N-ethyl-N′-3-dimethylaminopropyl carbodiimide, diphenyl phosphoryl azide and the like can be referred to. As the additive used in this reaction, for example, 1-hydroxybenzotriazole, N-hydroxysuccinimide and the like can be referred to. The alcohol, condensing agent and additive used in this reaction are used each in an amount of 0.5-10 mol and preferably 1-3 mol per mol of the compound of general formula [1k]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitriles such as acetonitrile and the like; amides such as N,N-dimethylformamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; and sulfoxides such as dimethyl sulfoxide and the like. The reaction is carried out usually at 0-200° C. and preferably at 25-150° C., for a period of 10 minutes to 24 hours.

The compound of general formula [1m] can be obtained by, for example, subjecting a compound of general formula [1l] to a de-esterification reaction in the presence of an acid. As the acid which can be used in this reaction according to the need, for example, hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, paratoluenesulfonic acid and the like can be referred to. The amount thereof is 1-50 mol and preferably 10-30 mol per mol of the compound of general formula [1l]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; nitriles such as acetonitrile and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; acetic acid; water; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. The reaction is carried out usually at 0-150° C. and preferably at 25-120° C., for a period of 30 minutes to 24 hours.

The compound of general formula [1la] can be obtained by, for example, subjecting a compound of general formula [1k] to an amidation reaction.

This reaction is a usual amidation reaction, which can be carried out by, for example, a method via an acid chloride, a method via an acid anhydride, a method using a base, a condensing agent and an additive, etc. In the case of using a base, a condensing agent and an additive, the amines which can be used in the reaction include primary amines such as methylamine, benzylamine, aniline, phenethylamine, aminothiazole and the like; secondary amines such as dimethylamine, diethylamine, di-n-propylamine and the like; cyclic amines such as piperidine, morpholine and the like; amino acids such as leucine, asparagine, aspartic acid, β-alanine, methionine and the like; compounds prepared by substituting the C-terminal carboxyl group may be substituted of the above-mentioned amino acids with an an unsubstituted or substituted alkyloxycarbonyl or carbamoyl group; compounds prepared by condensing 2 or 3 amino acids such as alanylalanine, leucylalanine or the like of which C-terminal carboxyl group may be substituted with an unsubstituted or substituted alkyloxycarbonyl or carbamoyl group; and the like. The amine is used in an amount of 0.5-10 mol and preferably 1-3 mol per mol of the compound of general formula [1k]. As the base which can be use in this reaction, organic amines such as dimethylaminopyridine, triethylamine, pyridine, N-methylmorphline and the like and alkali metal carbonates such as potassium carbonate, sodium carbonate and the like can be referred to, and the amount thereof is 0.5-10 mol and preferably 1-3 mol per mol of the compound of general formula [1k]. As the condensing agent, dicyclohexyl carbodiimide, diisopropyl carbodiimide, N-ethyl-N′-3-dimethylaminopropyl carbodiimide, diphenyl phosphoryl azide and the like can be referred to, and as the additive, 1-hydroxybenzotriazole, N-hydroxysuccinimide and the like can be referred to. The amounts of the condensing agent and the additive are both 0.5-10 mol and preferably 1-3 mol per mol of the compound of general formula [1k]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitriles such as acetonitrile and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. The reaction is carried out usually at a temperature of −20° C. to 150° C. and preferably at 0-120° C., for a period of 30 minutes to 24 hours.

The compound of general formula [1ma] can be obtained by, for example, subjecting a compound of general formula [1la] to a de-esterification reaction in the presence of an acid. As the acid which may be used in this reaction according to the need, for example, hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, paratoluenesulfonic acid and the like can be referred to, and the amount thereof is 1-50 mol and preferably 10-30 mol per mol of the compound of the general formula [1la]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; nitriles such as acetonitrile and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; acetic acid; water; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. The reaction is carried out usually at 0-150° C. and preferably at 25-120° C., for a period of 30 minutes to 24 hours.

[Production Process 2a]

[Production Process 2b]

wherein R³, R⁴, R⁵ and R⁶ are as defined above; R^(3a) and R^(4a), same or different, each represents hydrogen atom, halogen atom, cyano group, an unprotected or protected carboxyl group, an unprotected or protected hydroxyl group, or an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, aryl, amino, alkylamino, acylamino, carbamoyl or heterocyclic group or R^(3a) and R^(4a), taken conjointly, represent an oxo group; R^(5a) and R^(6a), same or different, each represents hydrogen atom, halogen atom, cyano group, an unprotected or protected carboxyl group, an unprotected or protected hydroxyl group, an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, aryl, amino, alkylamino, acylamino, carbamoyl or heterocyclic group or R^(5a) and R^(6a), taken conjointly with the terminal carbon atom to which R^(5a) and R^(6a) are combined, represent an alkenyl group; R^(3b) and R^(4b), same or different, each represents hydrogen atom, halogen atom, cyano group, an unprotected or protected carboxyl group, protected hydroxyl group, or an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, acyl, alkoxycarbonyl, aryl, amino, alkylamino, acylamino, carbamoyl or heterocyclic group or R^(3b) and R^(4b), taken conjointly, represent an oxo group; R^(5b) and R^(6b), same or different, each represents hydrogen atom, halogen atom, cyano group, an unprotected or protected carboxyl group, protected hydroxyl group, or an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, acyl, alkoxycarbonyl, aryl, amino, alkylamino, acylamino, carbamoyl or heterocyclic group or R^(5b) and R^(6b), taken conjointly with the terminal carbon atom to which R^(5b) and R^(6b) are combined, represent an alkenyl group; R^(2a) represents an unsubstituted or substituted acyl or sulfonyl group; R^(a) represents hydrogen atom, halogen atom, cyano group, nitro group, protected carboxyl group, protected hydroxyl group or an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl, aralkyl, alkoxy, aryloxy, acyl, alkoxycarbonyl, aryloxycarbonyl, carbamoyl, amino or heterocyclic group; R^(b) and R^(b′), same or different, each represents hydrogen atom, halogen atom, cyano group, nitro group, an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl, aralkyl or alkoxy group, protected amino group, or an unprotected or protected carboxyl group; X₀ represents chlorine, bromine or iodine atom; and R^(c) represents an unsubstituted or substituted alkyl, alkenyl, cycloalkyl or aryl group.

The compound of general formula [24] can be obtained by, for example, according to the method described in JP-A 53-44574, or the like. More concretely speaking, it can be obtained by reacting a compound [12] with a compound of general formula [8] in the presence or absence of a base and a dehydrating agent and subjecting the product to a dehydrating ring closure. Although the compound of general formula [8] which can be used in this reaction is not particularly critical, D-cysteine, L-cycteine, D-penicillamine and L-penicillamine of which C-terminal may optionally be protected and salts thereof can be referred to, for example. The compound of general formula [8] is used in an amount of 0.5-10 mol and preferably 1-2 mol per mol of the compound of general formula [12]. As the base which may be used according to the need, for example, organic amines such as dimethylaminopyridine, triethyamine, pyridine and the like; and alkali metal carbonates such as potassium carbonate, sodium carbonate and the like can be referred to, and the amount thereof is 0.5-10 mol and preferably 1-2 mol per mol of the compound of general formula [12]. As the dehydrating agent which may be used according to the need, zeolam, molecular sieve, calcium chloride, magnesium sulfate, diphosphorus pentoxide and the like can be referred to, and the amount thereof is 1-10 times (w/w) and preferably 1-2 times (w/w) as much as the weight of the compound of general formula [12]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitriles such as acetonitrile and the like; alcohols such as methanol, ethanol, isopropyl alcohol and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; water; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. The reaction is carried out usually at 0-150° C. and preferably at 20-120° C., for a period of 30 minutes to 24 hours.

The compound of general formula [25] can be obtained by, for example, subjecting a compound of general formula [24] to an acylation reaction or sulfonylation reaction in the presence or absence of a base. As the acylating agent which can be used in this reaction, for example, acetic anhydride, acetyl chloride, benzoyl chloride, pyrrole carbonyl chloride, thiazole carbonyl chloride and the like can be referred to. As the sulfonylating agent, methanesulfonyl chloride, benzenesulfonyl chloride and the like can be referred to, and the amount thereof is 0.5-10 mol and preferably 1-3 mol per mol of the compound of general formula [24]. As the base which may be used according to the need, organic amines such as dimethylaminopyridine, triethylamine, pyridine and the like; and alkali metal carbonates such as potassium carbonate, sodium carbonate and the like can be referred to, and the amount thereof is 0.5-10 mol and preferably 1-3 mol per mol of the compound of general formula [24].

The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitrites such as acetonitrile and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. The reaction is carried out usually at −20° C. to 150° C. and preferably at 0-120° C., for a period of 30 minutes to 24 hours.

The compound of general formula [26] can be obtained by de-protecting a compound of general formula [25] in the presence of an acid. As the acid which can be used in this reaction, mineral acids such as hydrochloric acid, sulfuric acid, hydrobromic acid and the like, and organic acids such as paratoluenesulfonic acid and the like can be referred to, and the amount thereof is 1-50 mol and preferably 5-20 mol per mol of the compound of general formula [25]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitrites such as acetonitrile and the like; alcohols such as methanol, ethanol, isopropyl alcohol and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; water; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. The reaction is carried out usually at 0-150° C. and preferably at 25-120° C., for a period of 30 minutes to 24 hours.

The compound of general formula [1o] can be obtained by reacting a compound of general formula [26a] with Wittig reagent or Honer Wadsworth Emmons reagent.

More concretely speaking, the compound of general formula [1o] can be obtained by reacting a compound of general formula [26a] with Wittig reagent which can be synthesized according to the method mentioned in Organic Syntheses Collective Volume, Vol. 5, Pages 751-754 (1973) or Honer Wadsworth Emmons reagent which can be synthesized according to the method mentioned in Organic Syntheses Collective Volume, Vol. 5, Pages 509-513 (1973). The Wittig reagent and the Honer Wadsworth Emmons reagent are used in an amount of 0.5-5 mol and preferably 1-2 mol per mol of the compound of general formula [26a]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitriles such as acetonitrile and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. The reaction is carried out usually at −78° C. to 120° C. and preferably at −20° C. to 30° C., for a period of 30 minutes to 24 hours. If desired, this reaction may be carried out in an atmosphere of inert gas such as argon or nitrogen.

The compound of general formula [1p] can be obtained by, for example, subjecting a compound of general formula [26a] and a compound of general formula [14] to Grignard reaction. The Grignard reagent used in this reaction can be synthesized according to the method mentioned in Organic Syntheses Collective Volume, Vol. 5, Page 226 (1955). Examples of the Grignard reagent include alkylmagnesium halides such as methylmagnesium bromide and the like and arylmagnesium halides such as phenylmagnesium bromide and the like.

In this reaction, the compound of general formula [14] is used in an amount of 0.5-5 mol and preferably 0.8-2 mol per mol of the compound of general formula [26a].

The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. The reaction is carried out usually at −20° C. to 120° C. and preferably at 0-70° C. for a period of 30 minutes to 24 hours. If desired, this reaction may be carried out in an atmosphere of inert gas such as argon or nitrogen.

The compound of general formula [1q] can be obtained by reacting a compound of general formula [26b] with a reductant in the presence or absence of a salt. As the salt which may be used according to the need, lithium chloride, magnesium chloride, calcium chloride and the like can be referred to, and the amount thereof is 1-10 mol per mol of the compound of general formula [26b]. As the reductant, sodium boron hydride, lithium boron hydride, aluminum diisobutyl hydride and the like can be referred to, and the amount thereof is 1-10 mol and preferably 1-2 mol per mol of the compound of general formula [26b]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and the like; ethers such as tetrahydrofuran, diethyl ether and the like; alcohols such as methanol, ethanol, isopropyl alcohol and the like; aromatic hydrocarbons such as toluene, benzene, xylene and the like; aliphatic hydrocarbons such as n-hexane, cyclohexane and the like; dimethyl sulfoxide, N,N-dimethylformamide, pyridine, water and the like. These solvents may be used alone or in mixture of two or more. The reaction is carried out usually at a temperature ranging from −78° C. to the reflux temperature of the used solvent and preferably at −78° C. to 30° C., for a period of 30 minutes to 24 hours.

The compound of general formula [1r] can be obtained by subjecting a compound of general formula [9] and a compound of general formula [1q] to a Mitsunobu reaction.

This reaction is carried out by using, for example, an azodicarbonyl compound such as diethylazo dicarboxylate, azodicarbonyl dipiperidine or the like and a triaryl phosphine such as triphenyl phosphine or the like or a trialkylphosphine such as tri-n-butyl phosphine or the like. The compound of general formula [9] is used in an amount of 1-5 mol and preferably 1-3 mol per mol of the compound of general formula [1q].

The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitriles such as acetonitrile and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. The reaction is carried out usually at −20° C. to 120° C. and preferably at 0° C. to 30° C., for a period of 30 minutes to 24 hours.

The compounds of general formulas [1a], [1b], [1c], [1d], [1e], [1f], [1g], [1h], [1i], [1j], [1k], [1l], [1la], [1m], [1ma], [1o], [1p], [1q] and [1r] which have been obtained in the above-mentioned manner can be converted to other compounds of general formula [1] by, for example, subjecting them to reactions known in themselves such as oxidation, reduction, rearrangement, substitution, halogenation, dehydration, hydrolysis, etc. or appropriately combining these reactions. The compounds of general formula [1] or salts thereof thus obtained can be isolated and purified by the conventional procedures such as extraction, crystallization and/or column chromatography, etc.

Next, the process for producing the compound of general formula [2] which is a starting material for producing the compound of the present invention will be described. The compound of general formula [2] can be obtained by, for example, the following processes.

[Production Process A]

[Production Process B]

[Production Process C]

[Production Process D]

[Production Process E]

wherein R^(a) represents hydrogen atom, halogen atom, cyano group, nitro group, protected carboxyl group, protected hydroxyl group or an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl, aralkyl, alkoxy, aryloxy, acyl, alkoxycarbonyl, aryloxycarbonyl, carbamoyl, amino or heterocyclic group; R^(b) and R^(b′), same or different, each represents hydrogen atom, halogen atom, cyano group, nitro group, an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl, aralkyl or alkoxy group, protected amino group or an unprotected or protected carboxyl group; R^(c) represents an unsubstituted or substituted alkyl, alkenyl, cycloalkyl or aryl group; X₀ represents chlorine, bromine or iodine atom; R^(d) and R^(e) represent hydrogen atom, an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl or aralkyl group; and R^(f) and R^(g) represent a protecting group for carboxyl group.

[Production Process A]

The compound of general formula [11] can be obtained by subjecting a compound of general formula [9] and a compound of general formula [10] to a Mitsunobu reaction.

This reaction can be carried out by, for example, using an azodicarbonyl compound such as diethylazo dicarboxylate, azodicarbonyl dipiperidine or the like and a triaryl phosphine such as triphenyl phosphine or the like or a trialkyl phosphine such as tri-n-butyl phosphine or the like. The compound of general formula [9] is used in an amount of 1-5 mol and preferably 1-3 mol per mol of the compound of general formula [10].

The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitriles such as acetonitrile and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. The reaction is carried out usually at −20° C. to 120° C. and preferably at 0° C. to 30° C., for a period of 30 minutes to 24 hours.

The compound of general formula [2a] can be obtained by, for example, de-protecting a compound of general formula [11] in the presence of an acid. As the acid which can be used in this reaction, mineral acids such as hydrochloric acid, sulfuric acid, hydrobromic acid and the like; and organic acids such as paratoluenesulfonic acid and the like can be referred to, and the amount thereof is 1-50 mol and preferably 5-20 mol per mol of the compound of general formula [11]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitrites such as acetonitrile and the like; alcohols such as methyl alcohol, ethyl alcohol, isopropyl alcohol and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; water; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. The reaction is carried out usually at 0-150° C. and preferably at 25-120° C., for a period of 30 minutes to 24 hours.

[Production Process B]

The compound of general formula [13] is obtained by reacting a compound of general formula [12] with Wittig reagent or Honer Wadsworth Emmons reagent.

More concretely speaking, the compound of formula [13] can be obtained by reacting a compound of general formula [12] with Wittig reagent which can be synthesized according to the method mentioned in Organic Syntheses Collective Volume, Vol. 5, Pages 751-754 (1973) or Honer Wadsworth Emmons reagent which can be synthesized according to the method mentioned in Organic Syntheses Collective Volume, Vol. 5, Pages 509-513 (1973). The Wittig reagent and the Honer Wadsworth Emmons reagent are used in an amount of 0.5-5 mol and preferably 1-2 mol per mol of the compound of general formula [12]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitriles such as acetonitrile and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. The reaction is carried out usually at −78° C. to 120° C. and preferably at −20° C. to 30° C., for a period of 30 minutes to 24 hours. If desired, this reaction may be carried out in an atmosphere of inert gas such as argon or nitrogen.

The compound of general formula [2b] can be obtained by, for example, de-protecting a compound of general formula [13] in the presence of an acid.

As the acid which can be used in this reaction, mineral acids such as hydrochloric acid, sulfuric acid, hydrobromic acid and the like, and organic acids such as paratoluenesulfonic acid, methanesulfonic acid and the like can be referred, and the amount thereof is 1-50 mol and preferably 5-20 mol per mol of the compound of general formula [13]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitrites such as acetonitrile and the like; alcohols such as methyl alcohol, ethyl alcohol, isopropyl alcohol and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; water; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. The reaction is carried out usually at 0-150° C. and preferably at 25-120° C., for a period of 30 minutes to 24 hours.

[Production Process C]

The compound of general formula [16] can be obtained by, for example, subjecting a compound of general formula [12] and a compound of general formula [14] to Grignard reaction. The Grignard reagent used in this reaction can be synthesized according to the method mentioned in Organic Syntheses Collective Volume, Vol. 5, Page 226 (1955). Examples of the Grignard reagent include alkylmagnesium halides such as methylmagnesium bromide and the like and arylmagnesium halides such as phenylmagnesium bromide and the like.

In this reaction, the compound of general formula [14] is used in an amount of 0.5-5 mol and preferably 0.8-2 mol per mol of the compound of general formula [12].

The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. The reaction is carried out usually at −20° C. to 120° C. and preferably at 0-70° C. for a period of 30 minutes to 24 hours. If desired, this reaction may be carried out in an atmosphere of inert gas such as argon or nitrogen.

The compound of general formula [2c] can be obtained by, for example, de-protecting a compound of general formula [16] in the presence of an acid. As the acid which can be used in this reaction, mineral acids such as hydrochloric acid, sulfuric acid, hydrobromic acid and the like, and organic acids such as paratoluenesulfonic acid, methanesulfonic acid and the like can be referred to, and the amount thereof is 1-50 mol and preferably 5-20 mol per mol of the compound of general formula [16]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitrites such as acetonitrile and the like; alcohols such as methyl alcohol, ethyl alcohol, isopropyl alcohol and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; water; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. The reaction is carried out usually at 0-150° C. and preferably at 25-120° C., for a period of 30 minutes to 24 hours.

[Production Process D]

The compound of general formula [19] can be obtained by, for example, the process mentioned in J. Org. Chem., Vol. 45, Pages 5399-5400 (1980), etc. More concretely speaking, it can be obtained by subjecting a compound of general formula [17] and a compound of general formula [18] to Robinson cyclization reaction. The compound of general formula [18] is used in an amount of 1-10 mol and preferably 2-4 mol per mol of the compound of general formula [17].

The reagent used in this reaction is, for example, an aldehyde such as isobutylaldehyde, cyclohexylaldehyde, 2-phenylpropionaldehyde and the like and a ketone such as methyl vinyl ketone, 3-penten-2-one and the like. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitrites such as acetonitrile and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. The reaction is carried out usually at −20° C. to 150° C. and preferably at 0-120° C., for a period of 30 minutes to 24 hours.

The compound of general formula [2d] can be obtained by, for example, reducing a compound of general formula [19]. This reaction may be carried out according to the conventional method for reducing carbon-carbon double bonds, for example, by the method of catalytic reduction using palladium-carbon, Raney nickel or platinum catalyst.

In the case of using a palladium-carbon catalyst, the catalyst is used in an amount of 0.01-1 time (w/w) and preferably 0.05-0.2 time (w/w) as much as the amount of the compound of general formula [19]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitrites such as acetonitrile and the like; alcohols such as methyl alcohol, ethyl alcohol, isopropyl alcohol and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; water; acetic acid, etc. These solvents may be used alone or in mixture of two or more. The reaction is carried out usually at −20° C. to 120° C. under normal pressure or elevated pressure, and preferably at 25-50° C., for a period of 30 minutes to 24 hours.

[Production Process E]

It is also possible to obtain the compound of general formula [21] according to the method mentioned in SYNTHETIC COMMUNICATIONS, Vol. 15, Pages 141-149 (1985). More concretely speaking, it can be obtained by subjecting a compound of general formula [20] and twice or more molar quantity, per mol of compound [20], of an acrylic ester represented by general formula [22] to Diekman condensation reaction. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitrites such as acetonitrile and the like; and amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like. These solvents may be used alone or in mixture of two or more. This reaction is carried out usually at −20° C. to 150° C. and preferably at 25-100° C., for a period of 30 minutes to 24 hours. If desired, the reaction may be carried out in an atmosphere of an inert gas such as argon or nitrogen.

The compound of general formula [2e] can be obtained by, for example, subjecting a compound of general formula [21] to a de-carboxylation reaction. The reagents used in this reaction are lithium chloride, lithium iodide, sodium chloride, pyridine and the like. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitrites such as acetonitrile and the like; alcohols such as methyl alcohol, ethyl alcohol, isopropyl alcohol and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; water; acetic acid; and the like. These solvents may be used alone or in mixture of two or more. This reaction is carried out usually at 25° C. to 250° C. and preferably at 100-190° C., for a period of 30 minutes to 24 hours.

Next, the processes for producing the compounds of the present invention will be explained.

In the production processes mentioned above, the compounds of general formulas [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [16], [17], [18], [19], [20], [21], [22], [24], [25], [26], [26a], [26b], [1a], [1b], [1c], [1f], [1g], [1i], [1k], [1l], [1la], [1m], [1ma], [1o], [1p], [1q], [1r], [2a], [2b], [2c], [2d] and [2e] can be put to use in the form of salts thereof, too. As salts thereof, the same salts as mentioned in the paragraph of the salts of compound of general formula [1] can be used.

In the production processes mentioned above, the compounds of general formulas [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [16], [17], [18], [19], [20], [21], [22], [24], [25], [26], [26a], [26b], [1a], [1b], [1c], [1f], [1g], [1i], [1k], [1l], [1la], [1m], [1ma], [1o], [1p], [1q], [1r], [2a], [2b], [2c], [2d] and [2e] can have isomers such as optical isomers, geometrical isomers and tautomers. In such cases, these isomers can also be used in the present invention. Further, solvated products, hydrates, and various crystal forms of these compounds can also be used. Further, in the compounds of [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [16], [17], [18], [19], [20], [21], [22], [24], [25], [26], [26a], [26b], [1a], [1b], [1c], [1f], [1g], [1i], [1k], [1l], [1la], [1m], [1ma], [1o], [1p], [1q], [1r], [2a], [2b], [2c], [2d] and [2e], some of the compounds can have an amino group, a hydroxyl group or a carboxyl group. It is also possible to protect these groups previously with conventional protecting groups and, after the reaction, to eliminate these protecting groups according to the methods known in themselves.

In cases where the compound of the present invention is a 1-thia-4,8-diazaspiro[4.5]decane derivative, such a compound can be synthesized according to the Production Processes 3 and 4 mentioned below, for example:

[Production Process 3]

[Production Process 4]

wherein R^(1h), R², k and n′ are as defined above; R^(13a) represents an unprotected or protected amino, alkylamino, arylamino, acylamino, alkoxycarbonylamino, arylsulfonylamino or alkylsulfonylamino group; R represents a protecting group for carboxyl group; X represents a protecting group for amino group; and Z represents halogen atom, alkylsulfonyloxy group or arylsulfonyloxy group.

The compound of general formula [35] can be obtained by, for example, the process mentioned in Yakugaku Zasshi, Vol. 91, No, 3, Pages 363-383 (1971), or the like. More concretely speaking, it can be obtained by reacting a compound of general formula [32] with an amine represented by general formula [33] or an ammonium salt and a compound represented by general formula [34] in the presence or absence of a dehydrating agent and/or a catalyst, and subjecting the reaction product to a dehydrating ring closure.

As the amine represented by general formula [33] or the ammonium salt which can be used in this reaction, for example, primary amines such as methylamine, benzylamine, aniline, phenethylamine or the like, amino acids such as leucine, asparagine, aspartic acid, β-alanine or the like, and ammonium salts such as ammonium carbonate, ammonium sulfate and the like can be referred to. The amine of general formula [33] or the ammonium salt is used in an amount of 1-10 mol and preferably 1-2 mol per mol of the compound of general formula [32]. The compound of general formula [34] is used in an amount of 1-10 mol and preferably 1-2 mol per mol of the compound of general formula [32]. As the dehydrating agent which can be used according to the need, zeolam, molecular sieve, calcium chloride, magnesium sulfate, diphosphorus pentoxide and the like can be referred to, and the amount thereof is 1-10 times (w/w) and preferably 1-2 times (w/w) as much as the-weight of the compound of general formula [32]. As the catalyst which can be used according to the need, paratoluenesulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid and the like can be referred to, and the amount thereof is 0.001-3 mol and preferably 0.01-0.1 mol per mol of the compound of general formula [32]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitrites such as acetonitrile and the like; alcohols such as methyl alcohol, ethyl alcohol, isopropyl alcohol and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. This reaction is carried out usually at 0-150° C. and preferably at 25-120° C. for a period of 30 minutes to 24 hours. If desired, this reaction may be carried out in an atmosphere of inert gas such as argon or nitrogen.

It is also possible to obtain the compound of general formula [36] by de-protecting a compound of general formula [35] in the presence or absence of an acid or a base.

As the acid which may be used in this reaction according to the need, hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, paratoluenesulfonic acid and the like can be referred to, and the amount thereof is 1-50 mol and preferably 10-30 mol per mol of the compound of general formula [35]. As the base which may be used in this reaction according to the need, organolithium compounds such as n-butyllithium, phenyllithium, lithium diisopropylamine and the like; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride and the like; alkali metal carbonates such as potassium carbonate, sodium carbonate and the like; and alkali hydroxides such as sodium hydroxide, potassium hydroxide and the like can be referred to, and the amount thereof is 1-50 mol and preferably 10-30 mol per mol of the compound of general formula [35]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; nitriles such as acetonitrile and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; water; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. This reaction is carried out usually at 0-150° C. and preferably at 25-110° C. for a period of 30 minutes to 24 hours.

The compound of general formula [1s] is obtained by, for example, subjecting a compound of general formula [36] to an acylation reaction or sulfonylation reaction in the presence or absence of a base.

As the acylating agent which can be used in this reaction, for example, acetic anhydride, acetyl chloride, benzoyl chloride, 4-isopropylbenzoyl chloride, ethylsuccinyl chloride and the like can be referred to. As the sulfonylating agent, methanesulfonyl chloride, benzenesulfonyl chloride and the like can be referred to. The amounts of said acylating agent and sulfonylating agent are 1-20 mol and preferably 2-6 mol per mol of the compound of general formula [36]. As the base which may be used according to the need, organic amines such as dimethylaminopyridine, triethylamine, pyridine and the like and alkali metal carbonates such as potassium carbonate, sodium carbonate and the like can be referred to, and the amount thereof is 0.5-10 mol and preferably 2-4 mol per mol of the compound of general formula [36]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitriles such as acetonitrile and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. The reaction is carried out usually at −20° C. to 150° C. and preferably at 0-120° C., for a period of 30 minutes to 24 hours.

The compound of general formula [37] can be obtained by, for example, the process mentioned in Yakugaku Zasshi, Vol. 91, No. 3, pages 363-383 (1971). More concretely speaking, it can be obtained by reacting a compound of general formula [32] with an amine represented by general formula [33] or an ammonium salt and mercaptoacetic acid in the presence or absence of a dehydrating agent and/or a catalyst, and subjecting the product to a dehydrating ring closure.

As the amines represented by general formula [33] which can be used in this reaction, primary amines such as methylamine, benzylamine, aniline, phenethylamine or the like and amino acids such as leucine, asparagine, aspartic acid, β-alanine or the like can be referred to. As the ammonium salts, ammonium carbonate, ammonium sulfate and the like can be referred to. The amine of general formula [33] or the ammonium salt is used in an amount of 1-10 mol and preferably 1-2 mol per mol of the compound of general formula [32]. The mercaptoacetic acid is used in amount of 1-10 mol and preferably 1-2 mol per mol of the compound of general formula [32]. As the dehydrating agent which can be used according to the need, zeolam, molecular sieve, calcium chloride, magnesium sulfate, diphosphorus pentoxide and the like can be referred to, and the amount thereof is 1-10 times (w/w) and preferably 1-2 times (w/w) as much as the weight of the compound of general formula [32]. As the catalyst which can be used according to the need, paratoluenesulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid and the like can be referred to, and the amount thereof is 0.001-3 mol and preferably 0.01-0.1 mol per mol of the compound of general formula [32]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitriles such as acetonitrile and the like; alcohols such as methyl alcohol, ethyl alcohol, isopropyl alcohol and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. This reaction is carried out usually at 0-150° C. and preferably at 25-120° C. for a period of 30 minutes to 24 hours. If desired, this reaction may be carried out in an atmosphere of inert gas such as argon or nitrogen.

The compound of general formula [38] can be obtained by, for example, reacting a compound of general formula [37] with a compound of general formula [39] in the presence of a base. As the base used in this reaction, for example, there can be referred to organolithium compounds such as n-butyllithium, phenyllithium, lithium diisopropylamide and the like; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride and the like; alkali metal carbonates such as potassium carbonate, sodium carbonate and the like; alkali hydroxides such as sodium hydroxide, potassium hydroxide and the like; etc. The base is used in an amount of 1-5 mol per mol of the compound of general formula [37]. The compound of general formula [39] is used in an amount of 1-10 mol and preferably 1-2 mol per mol of the compound of general formula [37]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; nitrites such as acetonitrile and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. This reaction is carried out usually at −78° C. to 150° C. and preferably at −50° C. to 120° C., for a period of 30 minutes to 24 hours. If desired, the reaction may be carried out in an atmosphere of inert gas such as argon or nitrogen.

It is also possible to obtain the compound of general formula [38] by the process mentioned in Yakugaku Zasshi, Vol. 91, No. 3, Pages 363-383 (1971), or the like. More concretely speaking, it can be obtained by reacting a compound of general formula [32] in the presence or absence of a dehydrating agent and/or a catalyst with an amine represented by general formula [33] or an ammonium salt and a compound represented by general formula [40] which can be synthesized according to the method mentioned in SYNTHETIC COMMUNICATIONS, Vol. 21, No. 2, Pages 249-263 (1991) or the like and subjecting the product to a dehydrating ring closure.

As the amine represented by general formula [33] used in this reaction, primary amines such as methylamine, benzylamine, aniline, phenethylamine and the like and amino acids such as leucine, asparagine, aspartic acid, β-alanine and the like can be referred to. As the ammonium salt, ammonium carbonate, ammonium sulfate and the like can be referred to. The amine of general formula [33] or the ammonium salt is used in an amount of 1-10 mol and preferably 1-2 mol per mol of the compound of general formula [32]. The compound of general formula [40] is used in an amount of 1-10 mol and preferably 1-2 mol per mol of the compound of general formula [32]. As the dehydrating agent, for example, zeolam, molecular sieve, calcium chloride, magnesium sulfate, diphosphorus pentoxide and the like can be referred to, and the amount thereof is 1-10 times (w/w) and preferably 1-2 times (w/w) as much as the amount of the compound of general formula [32]. As the catalyst which can be used according to the need, paratoluenesulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid and the like can be referred to, and the amount thereof is 0.001-3 mol and preferably 0.01-0.1 mol per mol of the compound of general formula [32]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitrites such as acetonitrile and the like; alcohols such as methyl alcohol, ethyl alcohol, isopropyl alcohol and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. This reaction is carried out usually at 0-150° C. and preferably at 25-120° C. for a period of 30 minutes to 24 hours. If desired, the reaction may be carried out in an atmosphere of inert gas such as argon or nitrogen.

Further, it is also possible to obtain the compound of general formula [38] by subjecting a compound of general formula [35] to an esterification reaction.

This reaction may be a usual esterification reaction, such as a method via an acid chloride, a method via an acid anhydride, a method using a base and an alkyl halide, a method using a condensing agent and an additive, etc. In a case where a base and an alkyl halide are used, the base which can be used include organic amines such as dimethylaminopyridine, triethylamine, pyridine, N-methylmorpholine and the like; alkali metal carbonates such as potassium carbonate, sodium carbonate and the like; etc. The amount of the base is 0.5-10 mol and preferably 1-3 mol per mol of the compound of general formula [35]. As the alkyl halide which can be used in this reaction, methyl iodide, ethyl iodide, benzyl bromide and the like can be referred to, and the amount thereof is 0.5-10 mol and preferably 1-3 mol per mol of the compound of general formula [35]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitrites such as acetonitrile and the like; amides such as N,N-dimethylformamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. The reaction is carried out usually at 0-200° C. and preferably at 25-150° C., for a period of 10 minutes to 24 hours. In a case where a condensing agent and an additive are used, the objective compound can be obtained by subjecting an alcohol such as ethanol, benzyl alcohol, tert-butanol or the like to a condensation reaction with a condensing agent and an additive. As the condensing agent used in this reaction, for example, dicyclohexyl carbodiimide, diisopropyl carbodiimide, N-ethyl-N′-3-dimethylaminopropyl carbodiimide, diphenyl phosphoryl azide and the like can be referred to. As the additive used in this reaction, for example, 1-hydroxybenzotriazole, N-hydroxysuccinimide and the like can be referred to. The alcohol, condensing agent and additive used in this reaction are used each in an amount of 0.5-10 mol and preferably 1-3 mol per mol of the compound of general formula [35]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitriles such as acetonitrile and the like; amides such as N,N-dimethylformamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. The reaction is carried out usually at 0-200° C. and preferably at 25-150° C., for a period of 10 minutes to 24 hours.

The compound of general formula [41] can be obtained by de-protecting a compound of general formula [38] in the presence or absence of an acid or a base.

As the acid which may be used in this reaction according to the need, hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, paratoluenesulfonic acid and the like can be referred to, and the amount thereof is 1-50 mol and preferably 10-30 mol per mol of the compound of general formula [38]. As the base which may be used in this reaction according to the need, organolithium compounds such as n-butyllithium, phenyllithium, lithium diisopropylamide and the like; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride and the like; alkali metal carbonates such as potassium carbonate, sodium carbonate and the like; and alkali hydroxides such as sodium hydroxide, potassium hydroxide and the like can be referred to, and the amount thereof is 1-50 mol and preferably 1-30 mol per mol of the compound of general formula [38].

In a case where X is a tert-butyloxycarbonyl group and R is an ethyl group, the acids which can be used are hydrochloric acid, sulfuric acid, trifluoroacetic acid and the like, and the amount thereof is 1-50 mol and preferably 10-30 mol per mol of the compound of general formula [38]. In a case where X is a 9-fluorenylmethoxycarbonyl group and R is a tert-butyl group, the bases which can be used are piperidine, morpholine, dimethylaminopyridine and the like, and the amount thereof is 1-30 mol and preferably 1-5 mol per mol of the compound of general formula [38]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitriles such as acetonitrile and the like; alcohols such as methyl alcohol, ethyl alcohol, isopropyl alcohol and the like; amides such as N,N-dimethylformamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; water; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. This reaction is carried out usually at 0-200° C. and preferably at 20-70° C. for a period of 10 minutes to 5 hours.

The compound of general formula [42] can be obtained by, for example, subjecting a compound of general formula [41] to an acylation reaction or a sulfonylation reaction in the presence or absence of a base.

As the acylating agent which can be used in this reaction, for example, acetic anhydride, acetyl chloride, benzoyl chloride, ethylsuccinyl chloride and the like can be referred to. As the sulfonylating agent, methanesulfonyl chloride, benzenesulfonyl chloride and the like can be referred to. The amount of said acylating agent and sulfonylating agent is each 0.5-10 mol and preferably 1-3 mol per mol of the compound of general formula [41]. As the base used in this reaction, organic amines such as dimethylaminopyridine, triethylamine, pyridine and the like and alkali metal carbonates such as potassium carbonate, sodium carbonate and the like can be referred to, and the amount thereof is 0.5-10 mol and preferably 1-3 mol per mol of the compound of general formula [41]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitriles such as acetonitrile and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. The reaction is carried out usually at −20° C. to 150° C. and preferably at 0-120° C., for a period of 30 minutes to 24 hours.

The compound of general formula [42] can be obtained by, for example, subjecting a compound of general formula [41] to an alkylation reaction in the presence of a base. As the alkylating agent which can be used in this reaction, for example, methyl iodide, benzyl bromide and the like can be referred to, and the amount thereof is 1-20 mol and preferably 1-4 mol per mol of the compound of general formula [41]. As the base used in this reaction, organic amines such as dimethylaminopyridine, triethylamine, pyridine and the like and alkali metal carbonates such as potassium carbonate, sodium carbonate and the like can be referred to, and the amount thereof is 2-20 mol and preferably 2-4 mol per mol of the compound of general formula [41]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitriles such as acetonitrile and the like; alcohols such as methyl alcohol, ethyl alcohol, isopropyl alcohol and the like; amides such as N,N-dimethylformamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. The reaction is carried out usually at 0-200° C. and preferably at 25-150° C., for a period of 10 minutes to 24 hours.

The compound of general formula [42] can be obtained by, subjecting a compound of general formula [41] to a nitrosation reaction in the presence of a base and then reducing the product. The nitrosation reaction can be carried out according to the procedure mentioned in Organic Syntheses Collective Volume, Vol. 2, Page 211 (1943). As the nitrosating agent, for example, nitrous acid and the like can be used. The nitrosating agent is used in an amount of 1-10 mol and preferably 1-4 mol per mol of the compound of general formula [41]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitriles such as acetonitrile and the like; alcohols such as methyl alcohol, ethyl alcohol, isopropyl alcohol and the like; amides such as N,N-dimethylformamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; water; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. The reaction is carried out usually at 0-200° C. and preferably at 0-100° C., for a period of 10 minutes to 24 hours.

The reduction as a subsequent step can be carried out according to the description of Organic Syntheses Collective Volume, Vol. 2., Page 211 (1943). That is, the objective product can be obtained by reacting the nitroso compound synthesized from the compound of general formula [41] with a reductant such as zinc powder. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitriles such as acetonitrile and the like; alcohols such as methyl alcohol, ethyl alcohol, isopropyl alcohol and the like; amides such as N,N-dimethylformamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; water; and acetic acid. These solvents may be used alone or in mixture of two or more. The reaction is carried out usually at 0-200° C. and preferably at 0-100° C., for a period of 30 minutes to 24 hours.

The compound of general formula [1s] can be obtained by, for example, subjecting a compound of general formula [42] to a de-esterification reaction in the presence or absence of an acid or a base.

As the acid which can be used in this reaction according to the need, for example, hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, paratoluenesulfonic acid and the like can be referred to. The amount thereof is 1-50 mol and preferably 10-30 mol per mol of the compound of general formula [42]. As the base used in this reaction according to the need, for example, there can be referred to organolithium compounds such as n-butyllithium, phenyllithium, lithium diisopropylamide and the like; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride and the like; alkali metal carbonates such as potassium carbonate, sodium carbonate and the like; alkali hydroxides such as sodium hydroxide, potassium hydroxide and the like; etc. The base is used in an amount of 1-50 mol and preferably 10-30 mol per mol of the compound of general formula [42]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; nitrites such as acetonitrile and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; acetic acid; water; alcohols such as methyl alcohol, ethyl alcohol, isopropyl alcohol and the like; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. The reaction is carried out usually at 0-150° C. and preferably at 25-120° C., for a period of 30 minutes to 24 hours.

The compound of general formula [1t] can be obtained by subjecting a compound of general formula [1s] to an amidation reaction.

This reaction may be a usual amidation reaction, such as a method via an acid chloride, a method via an acid anhydride, a method using a base, a condensing agent and an additive, etc. For example, in the case of using a base, a condensing agent and an additive, the amines which can be used in the reaction include primary amines such as methylamine, benzylamine, aniline, phenethylamine, aminothiazole and the like; secondary amines such as dimethylamine, diethylamine, di-n-propylamine and the like; cyclic amines such as piperidine, morpholine and the like; and amino acids such as leucine, asparagine, aspartic acid, β-alanine and the like. The amine is used in an amount of 0.5-10 mol and preferably 1-3 mol per mol of the compound of general formula [1s]. As the base which can be use in this reaction, organic amines such as dimethylaminopyridine, triethylamine, pyridine, N-methylmorpholine and the like and alkali metal carbonates such as potassium carbonate, sodium carbonate and the like can be referred to, and the amount thereof is 0.5-10 mol and preferably 1-3 mol per mol of the compound of general formula [1s]. As the condensing agent, dicyclohexyl carbodiimide, diisopropyl carbodiimide, N-ethyl-N′-3-dimethylaminopropyl carbodiimide, diphenyl phosphoryl azide and the like can be referred to, and as the additive, 1-hydroxybenzotriazole, N-hydroxysuccinimide and the like can be referred to. The amounts of the condensing agent and the additive are both 0.5-10 mol and preferably 1-3 mol per mol of the compound of general formula [1s]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve nd the like; esters such as methyl acetate, ethyl acetate and the like; nitriles such as acetonitrile and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. The reaction is carried out usually at a temperature of −20° C. to 150° C. and preferably at 0-120° C., for a period of 30 minutes to 24 hours.

The compound of general formula [1u] can be obtained by, for example, oxidizing a compound of general formula [1s].

As the oxidant which can be used in this reaction, for example, peracids such as peracetic acid, trifluoro-peracetic acid, perbenzoic acid, m-chloroperbenzoic acid and the like; hydrogen peroxide; chromic acid; potassium permanganate and the like can be referred to. The oxidant is used in an amount of 0.5-5 mol and preferably 1-3 mol per mol of the compound of general formula [1s]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; alcohols such as methanol, ethanol and the like; esters such as methyl acetate, ethyl acetate and the like; nitriles such as acetonitrile and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; water; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. This reaction is carried out usually at a temperature ranging from 0° C. to reflux temperature of the used solvent and preferably at 0-30° C., for a period of 30 minutes to 24 hours.

The compound of general formula [1v] can be obtained by subjecting a compound of general formula [1u] to an amidation reaction. This reaction may be a usual amidation reaction, such as a method via an acid chloride, a method via an acid anhydride, a method using a base, a condensing agent and an additive, etc. For example, in the case of using a base, a condensing agent and an additive, the amines which can be used in the reaction include primary amines such as methylamine, benzylamine, aniline, phenethylamine, aminothiazole and the like; secondary amines such as dimethylamine, diethylamine, di-n-propylamine and the like; cyclic amines such as piperidine, morpholine and the like; and amitno acids such as leucine, asparagine, aspartic acid, β-alanine and the like. The amine is used in an amount of 0.5-10 mol and preferably 1-3 mol per mol of the compound of general formula [1u]. As the base which can be used in this reaction, organic amines such as dimethylaminopyridine, triethylamine, pyridine, N-methylmorpholine and the like and alkali metal carbonates such as potassium carbonate, sodium carbonate and the like can be referred to, and the amount thereof is 0.5-10 mol and preferably 1-3 mol per mol of the compound of general formula [1u]. As the condensing agent, dicyclohexyl carbodiimide, diisopropyl carbodiimide, N-ethyl-N′-3-dimethylaminopropyl carbodiimide, diphenyl phosphoryl azide and the like can be referred to, and as the additive, 1-hydroxybenzotriazole, N-hydroxysuccinimide and the like can be referred to. The amounts of the condensing agent and the additive are both 0.5-10 mol and preferably 1-3 mol per mol of the compound of general formula [1u]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitrites such as acetonitrile and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. The reaction is carried out usually at a temperature of −20° C. to 150° C. and preferably at 0-120° C., for a period of 30 minutes to 24 hours.

The compound of general formula [1v] can be obtained by, for example, oxidizing a compound of general formula [1t].

As the oxidant which can be used in this reaction, for example, peracids such as peracetic acid, trifluoro-peracetic acid, perbenzoic acid, m-chloroperbenzoic acid and the like; hydrogen peroxide; chromic acid; potassium permanganate and the like can be referred to. The oxidant is used in an amount of 0.5-5 mol and preferably 1-3 mol per mol of the compound of general formula [1t]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; alcohols such as methanol, ethanol and the like; esters such as methyl acetate, ethyl acetate and the like; nitrites such as acetonitrile and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; water; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. This reaction is carried out usually at a temperature ranging from 0° C. to reflux temperature of the used solvent and preferably at 0-30° C., for a period of 30 minutes to 24 hours.

The compounds of general formulas [1s], [1t], [1u] and [1v] which have been obtained in the above-mentioned manner can be converted to other compounds of general formula [1] by, for example, subjecting them to reactions known in themselves such as oxidation, reduction, rearrangement, substitution, halogenation, dehydration, hydrolysis, etc. or appropriately combining these reactions. The compounds of general formula [1s], [1t], [1u] and [1v] or salts thereof thus obtained can be isolated and purified by the conventional procedures such as extraction, crystallization and/or column chromatography, etc.

By converting the compound of [1s] or [1u], for example, to an acid halide by the conventional method, reacting the acid halide with diethyl malonate and magnesium chloride in the presence of a base such as triethylamine and then subjecting the product to hydrolysis and decarboxylation, there can be obtained a compound in which R^(13a) is an an unsubstituted or substituted alkyl group. By converting the compound of [1s] or [1u] to an acid halide by the conventional method and then reacting the acid halide with alkylmercaptan, there can be obtained a compound in which R^(13a) is an unsubstituted or substituted alkylthio group. Further, by converting the compound of [1s] or [1u] to an acid halide by the conventional method and then subjecting the acid halide to Friedel-Crafts reaction with an aryl or heterocyclic group in the presence of an acid such as aluminum chloride or the like, there can be obtained a compound in which R^(13a) is an unsubstituted or substituted aryl or heterocyclic group.

The compound of general formula [32] which is a starting compound for production of the compound of the present invention can be produced according to the method described in, for example, Synthesis, Page 48 (1986) or the like or a similar method.

In the production processes mentioned above, the compounds of general formulas [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [1s], [1t] and [1u] can be used in the form of a salt, too. As said salt, the same ones as mentioned in the paragraph of salts of the compound of general formula [1] can be referred to.

The compounds of general formulas [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [1s], [1t], [1u] and [1v] can be converted to salts thereof. As said salts, the same ones as mentioned in the paragraph of general formula [1] can be referred to.

In the above-mentioned production processes, some of the compounds of general formulas [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [1s], [1t] and [1u] have isomers such as optical isomer, geometrical isomer, tautomer, etc. In such cases, these isomers are also usable in the present invention. Further, solvated products, hydrates and various crystal forms of these compounds are also usable. In the compounds of general formulas [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [1s], [1t], [1u] and [1v], some compounds have an amino group, a hydroxyl group, a mercapto group or a carboxyl group. It is possible, if desired, to protect these groups previously with a usual protecting group and, after the reaction, to eliminate the protecting group according to a method known in itself.

It is also possible to obtain the compounds of general formulas [1w], [1x] and [1y] by, for example, the following Production Processes 5-7.

Production Process 5

wherein

Y⁴ represents O or NH; q reprsesents 0, 1, 2 or 3, provided that when q is zero, Y⁴ represents NH; E⁴ represents amino acid residue; and R^(1h′) represents a roup of the following general formula:

R^(15′)—Y^(3′)—

wherein Y^(3′) represents carbonyl group; and R^(15′) represents hydrogen atom, cyano group, protected carboxyl, hydroxyl or mercapto group or an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl, alkoxy, alkylthio, alkylsulfonyl, arylsulfonyl, sulfamoyl, acyl, acyloxy, alkoxycarbonyl, aryloxycarbonyl, amino, carbamoyl, carbamoyloxy or heterocyclic group; or a group of the following general formula:

R¹⁶—(E³)_(s)—

wherein R¹⁶ represents hydrogen atom or a protecting group for amino group; E³ represents amino acid residue; and s represents 2 or 3; and X represents a protecting group for amino group; and R^(2′) represents hydrogen atom or an unsubstituted or substituted acyl group.

The amino acid-bounded resin of general formula [44] can be obtained by reacting a resin of general formula [43] with an amino acid derivative, followed by de-protection. As the resin usable in this reaction, the resins conventionally used in the solid phase method can be referred to, of which examples include benzhydrylamine resin, 4-methylbenzhydrylamine resin, Rink amide resin, oxymethyl resin, oxymethylphenoxymethyl resin and the like. As the amino acid derivatives usable in this reaction, there can be referred to those amino acid derivatives in which t-butyloxycarbonyl (Boc) group or 9-fluorenylmethoxycarbonyl (Fmoc) group is used as protecting group for an α-amino acid, those in which t-butyl ester group, benzyl ester group, cyclohexyl ester group or the like is used as protecting group for the side chain functional group such as the side chain carboxyl group of aspartic acid or glutamic acid; those in which t-butyl group, benzyl group, 2,6-dibromobenzyl group or the like is used as a protecting group for the side chain hydroxyl group of serine, threonine, tyrosine; those in which trityl group, acetamidomethyl group, t-butyl group or the like is used as a protecting group for the side chain thiol group of cycteine; etc. Among these amino acid derivatives, Fmoc-amino acids are preferred.

(1) An amino acid-bounded resin with protected N-terminal can be obtained by condensing a resin with an amino acid derivative. Concretely speaking, it can be obtained by introducing a resin into a reactor, adding a solvent thereto to swell the resin, filtering off the solvent, adding an amino acid derivative and a condensation reagent, again adding a solvent, and then carrying out a reaction. As the condensation reagent used in this reaction, dicyclohexyl carbodiimide, diisopropyl carbodiimide, benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBroP) and the like can be referred to, and the amount thereof is 1-10 equivalents per equivalent of amino group in the resin. In the case of using PyBOP or PyBroP, an amine such as diisopropylethylamine, triethylamine or the like may be added, if desired, in an amount of 1-5 equivalents per equivalent of the condensing agent. It is also allowable to add 0.5-5 equivalents of an ester-activator such as N-hydroxybenzotriazole, N-hydroxy-7-azabenzotriazole or the like per equivalent of the condensation reagent. As the solvents used in this reaction, N,N-dimethylformamide, dichloromethane, chloroform, N-methylpyrrolidone and the like can be referred to. Although the amount of the solvent is not particularly critical, 5-100 ml and preferably 5-20 ml of solvent is used per gram of the resin when used for swelling the resin, and 5-100 ml, preferably 5-50 ml, of solvent is used per gram of the resin when used for reaction. This reaction is carried out usually at 10-40° C. and preferably at 20-30° C. for a period of 5-120 minutes.

(2) An amino acid-bounded resin with de-protected N-terminal can be obtained by reacting an amino acid-bounded resin having a protected N-terminal with a de-protecting agent and thereby eliminating the protecting group for a-amino acid. Concretely speaking, a peptide-bonding resin having a protected N-terminal is reacted in the presence of an acid or a base in the resence or absence of a solvent. The de-protecting group used in this reaction is properly selected in accordance with the kind of protecting group for α-amino acid. For example, in the case where the protecting group for α-amino acid to be eliminated is a Boc group, an acid such as trifluoroacetic acid, methanesulfonic acid and the like is used. In the case where the protecting group for α-amino acid to be eliminated is a Fmoc group, a base such as piperidine, 1,8-diazabicyclo[5.4.0]undec-7-ene or the like is used. The solvent used in this reaction is not critical so far as the solvent exercises no adverse influence on the reaction. When an acid is used for the elimination, dichloromethane, dichloroethane and the like can be used. When a base is used for the elimination, N,N-dimethylformamide, N-methylpyrrolidone and the like can be used. When a solvent is used, the solvent may be used in a proportion of 5-20 ml per one gram of the resin. The reaction is carried out usually at 10-40° C. and preferably at 20-30° C. for a period of 5-120 minutes.

For combining two or more amino acid residues, the procedure mentioned above is repeated.

The resin of general formula [45] can be obtained by reacting an amino acid-bounded resin of general formula [44] with a compound of general formula [47], followed by de-protection. This reaction can be effected in the same manner as above.

The resin of general formula [46] can be btained by acylating a resin of general formula [45]. This reaction can be effected in the same manner as above. In a case where the functional group of the compound bonded to the resin of formula [46] is protected, conversion to other compound can be carried out by de-protection followed by acylation, sulfonylation or the like. These reactions may be effected in the same manner as above.

The compound of general formula [1w] can be obtained by treating a resin of general formula [46] in the presence of an acid to remove the resin therefrom. The acid used in this reaction is properly selected in accordance with the combination of the used resin and the protecting group for amino group. The acids include, for example, trifluoromethanesulfonic acid, anhydrous hydrogen fluoride, trifluoroacetic acid and the like. The solvent used in this reaction is not critical so far as the solvent exercises no adverse influence on the reaction. For example, dichloromethane is used for this purpose. Although the amount of the solvent is not critical, 5-100 ml of the solvent may be used per gram of the resin. The reaction is carried out at −10° C. to 40° C. and preferably at 0-20° C., for a period of 30-300 minutes.

Production Process 6

wherein

Y⁵ represents O or NH; q represents 0, 1, 2 or 3; E² represents amino acid residue; k represents 1, 2 or 3; and R^(1h′) represents a group of the following formula:

R^(11′)—Y^(2′)—

wherein Y^(2′) represents carbonyl group; and R^(11′) represents hydrogen atom, cyano group, protected carboxyl, hydroxyl or mercapto group, or an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl, alkoxy, alkylthio, alkylsulfonyl, arylsulfonyl, sulfamoyl, acyl, acyloxy, alkoxycarbonyl, aryloxycarbonyl, amino, carbamolyl, carbamoyloxy or heterocyclic group; or a group of the following general formula:

R¹²—(E¹)_(j)—

wherein R¹² represents hydrogen atom or a protecting group for amino group; R¹⁴ represents hydroxyl group or amino group; E¹ represents amino acid residue; and j represents 2 or 3; and X represents a protecting group for amino group; and R^(2′) represents hydrogen atom or an unsubstituted or substituted acyl group.

The resin of general formula [48] can be obtained by reacting a resin of general formula [44a] with a compound of general formula [50], followed by de-protection. This reaction may be carried out in the same manner as mentioned in the paragraph of Production Process 5.

The resin of general formula [49] can be obtained by acylating a resin of the general formula [48]. This reaction may be carried out in the same manner as above. In a case where the functional group of the compound bonded to the resin of formula [48] is protected, conversion to other compound can be carried out by de-protection, followed by acylation, sulfonylation or the like. These reaction may be carried out in the same manner as above.

The compound of the general formula [1x] can be obtained by treating a resin of general formula [49] in the presence of an acid to remove the resin therefrom. This reaction may be carried out in the same manner as mentioned in the paragraph of Production Process 5.

Production Process 7

wherein

Y⁵ represents O or NH; k represents 1, 2, or 3; q represents 0, 1, 2 or 3; u represents 0, 1, 2 or 3; and R^(1h′) represents a group of the following general formula:

R^(11′)—Y^(2′)—

wherein Y^(2′) represents carbonyl group; and R^(11′) represents hydrogen atom, cyano group, protected carboxyl, hydroxyl or mercapto group, or an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl, alkoxy, alkylthio, alkylsulfonyl, arylsulfonyl, sulfamoyl, acyl, acyloxy, alkoxycarbonyl, aryloxycarbonyl, amino, carbamoyl, carbamoyloxy or heterocyclic group; or a group of the following general formula:

R¹²—(E¹)_(j)—

wherein R¹² represents hydrogen atom or a protecting group for amino group; E¹ represents amino acid residue; and j represents 2 or 3; and R^(2′) represents hydrogen atom, or an unsubstituted or substituted acyl group; R¹⁴ represents hydroxyl group or amino group; E² and E⁵ each represents amino acid residue; and X represents a protecting group for amino group.

The resin of general formula [51] can be obtained by reacting a resin of general formula [44b] with a compound of general formula [53], followed by de-protection. This reaction may be carried out in the same manner as in the description of Production Process 5.

The resin of general formula [52] can be obtained by acylating a resin of general formula [51]. This reaction may be carried out in the same manner as above. In a case where the functional group of the compound bonded to the resin of formula [52] is protected, conversion to other compounds can be carried out by de-protection, followed by acylation, sulfonylation, etc. These reactions may be carried out in the same manner as above.

The compound of general formula [1y] can be obtained by treating a resin of general formula [52] in the presence of an acid to remove the resin therefrom. This reaction may be carried out in the same manner as mentioned in the paragraph of Production Process 5.

The compound of general formula [55] which is a starting compound for production of the compound of the present invention can be obtained, for example, in the following manner.

[Production Process F]

wherein X represents a protecting group for amino group; R^(3′), R^(4′), R⁵ and R⁶ are as defined above; and R^(2′) represents an unsubstituted or substituted acyl group.

The compound of general formula [54] can be obtained according to, for example, the process mentioned in JP-A 53-44574, or the like. More concretely speaking, it can be obtained by reacting a compound of general formula [32] with a compound of general formula [8a] in the presence or absence of a base, a dehydrating agent and a catalyst, and subjecting the product to a dehydrating ring closure. Although the compound of general formula [8a] used in this reaction is not particularly critical, D-cysteine, L-cysteine, D-penicillamine and L-penicillamine and salts thereof can be referred to, for example. The compound of general formula [8a] is used in an amount of 0.5-10 mol and preferably 1-2 mol per mol of the compound of general formula [32]. As the base which may be used according to the need, for example, organic amines such as dimethylaminopyridine, triethylamine, pyridine and the like, alkali metal carbonates such as potassium carbonate, sodium carbonate and the like; etc. can be referred to, and the amount thereof is 0.5-10 mol and preferably 1-2 mol per mol of the compound of general formula [32]. As the dehydrating agent which may be used according to the need, zeolam, molecular sieve, calcium chloride, magnesium sulfate, diphosphorus pentoxide and the like can be referred to, and the amount thereof is 1-10 times (w/w) and preferably 1-2 times (w/w) as much as the weight of the compound of general formula [32]. As the catalyst which may be used according to the need, paratoluene-sulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid and the like can be referred to, and the amount thereof is 0.001-1 mol and preferably 0.01-0.1 mol per mol of the compound of general formula [32]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitriles such as acetonitrile and the like; alcohols such as methyl alcohol, ethyl alcohol, isopropyl alcohol and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; water; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. This reaction is carried out usually at 0-150° C. and preferably at 20-120° C., for a period of 30 minutes to 24 hours.

The compound of general formula [55] can be obtained by, for example, acylating a compound of general formula [54] in the presence or absence of a base. As the acylating agent which can be used in this reaction, for example, acetic anhydride, acetyl chloride, benzoyl chloride, pyrrolecarbonyl chloride, thiazolecarbonyl chloride and the like can be referred to. The amount of said acylating agent is 0.5-10 mol and preferably 1-3 mol per mol of the compound of general formula [54]. As the base which may be used according to the need, organic amines such as dimethylaminopyridine, triethylamine, pyridine and the like and alkali metal carbonates such as potassium carbonate, sodium carbonate and the like can be referred to, and the amount thereof is 0.5-10 mol and preferably 1-3 mol per mol of the compound of general formula [54]. The solvent used in this reaction is not particularly critical so far as the solvent exercises no adverse influence upon the reaction. Examples of the solvent which can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitriles such as acetonitrile and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more. The reaction is carried out usually at −20° C. to 150° C. and preferably at 0-120° C., for a period of 30 minutes to 24 hours.

It is also possible, if desired, to eliminate the protecting group just after the compound [55] has been obtained and thereafter to convert it to other protecting group.

In the production processes mentioned above, the compounds of general formulas [8a], [32], [43], [44], [44a], [44b], [45], [46], [47], [48], [49], [50], [51], [52], [53], [54], [55], [1w], [1x] and [1y] can be used in the form of a salt, too. As said salt, the same ones as mentioned in the paragraph of salts of the compound of general formula [1] can be referred.

In the above-mentioned Production Processes 5, 6, 7 and F, some of the compounds of general formulas [8a], [32], [43], [44], [44a], [44b], [45], [46], [47], [48], [49], [50], [51], [52], [53], [54], [55], [1w], [1x] and [1y] have isomers such as optical isomer, geometrical isomer, tautomer, etc. In such cases, these isomers are also usable in the present invention. Further, solvated products, hydrates and various crystal forms of these compounds are also usable.

In the compounds of general formulas [8a], [32], [43], [44], [44a], [44b], [45], [46], [47], [48], [49], [50], [51], [52], [53], [54], [55], [1w], [1x] and [1y], some compounds have an amino group, a hydroxyl group, a mercapto group or a carboxyl group. It is possible, if desired, to protect these groups with a usual protecting group previously and, after the reaction, to eliminate the protecting group according to a method known in itself.

When the compound of the present invention is used as a medical drug, conventional adjuvants for preparations such as an excipient, a carrier, a diluent and the like may be appropriately mixed into the composition, and the preparations thus obtained can be orally or non-orally administered in the form of tablet, capsule, powder, syrup, granule, pill, suspension, emulsion, solution, powdery preparation, suppository, ointment, injection and the like according to usual ways. The method, dosage and frequency of administration can properly be selected according to age, body weight and symptom of the patient. Usually, in case of adult patients, the preparation is orally or non-orally (for example, by injection, instillation, rectal application and the like) administered at a dosage of 0.1 to 100 mg/kg per day, at once or in several portions.

Next, pharmacological activities of typical compounds of the present invention will be mentioned below.

[Testing Method]

Test Example 1: Preparation of Transfectant

A reporter plasmid was prepared according to the method of R. I. Scheinman et al. [Mol. Cell. Biol., Vol. 15, Pages 943-953 (1995)]. That is, a plasmid p(TRE)₅TK-Luc was constructed by connecting a promoter of thymidine kinase (TK) at an upstream site of luciferase (Luc) gene which is a reporter gene and a 5-times repeated TRE sequence at a further upstream site thereof. The plasmid was co-transfected simultaneously with p3′SS plasmid (prepared by Stratagene Co.) by the electrotranspolation method onto mouse 3T3 fibroblast (ATCC: CCL-163) cultured in a Dulbecco's modified Eagle's medium (DMEM) containing 10% fetal calf serum (FCS). Then the cells were cultured in DMEM containing 10% FCS and 100 μg/ml of Hygromycin B. Using the expression of Hygromycin-resistant gene contained in p3′SS as an indicator, cell strains of the transfectant into which the objective plasmid had been introduced stably were selected. Furthermore in the test mentioned below, cell strains showing expression of Luc gene under stimulation of 12-O-tetradecanoylphorbol 13-acetate (TPA, prepared by Sigma Co.) were used, and DMEM containing 10% FCS and 100 μg/ml of Hygromycin B was used for the culture of cells.

Test Example 2: Luciferase Assay

The cells prepared above were suspended in culture medium, and plated 96 well-plate at 1×10⁴ cells/0.1 ml. After culturing it overnight, 50 μl of test compounds solution and 40 μl of culture medium were added, and incubated. After one hour 10 μl of 200 ng/ml TPA solution was added and the culture was continued for an additional 16 hours to stimulate the cells. The end of cluture, the cells were recovered, and cell lysis solutions were obtained. The Luc activity of the cell lysates was measured with a chemilluminescent detection kit (Pica Gene; manufactured by Toyo Ink Co.). The suppressive effect of each test compound could be assessed as a decrease of Luc activity, and the inhibition rate (%) was calculated according to the following formula:

Inhibition rate (%)=(1−Luc activity of cells to which the compound is added/Luc activity of cells to which the compound is not added)×100

Test Example 3: XTT Assay (Cytotoxicity Test)

The same culture plate as above was prepared, and test compound and TPA were added under the same conditions as above, after which a culture was carried out for 16 hours. The end of cluture, XTT reagent prepared according to the method of D. A. Scudievo [Cancer Res., Vol. 48, Pages 4827-4833 (1988)] was added and made to react for a prescribed period of time. Then, the amount of formazan formed by alive cells was analyzed by measuring absorbance at 450 nm using a micro plate reader. In this test, a decrease in absorbance is observed when the test compounds show a cytotoxicitic or a growth inhibitory activity. Cell viability (T/C %) was determined according to the following formula:

Cell Viability Rate (T/C %)=(Absorbance of well to which compound is added/Absorbance of well to which the compound was not added)×100

The results are shown in Table 52.

TABLE 52 Inhibition Cell Example Concentration rate viability No. μg/ml (%) (%)  1  50 80 80  2 100 38 81  6 (3) 100 91 83  6 (5)  30 60 106 12 100 74 84 13 100 40 80 14  30 23 100  15 100 79 87 16 (11)  30 65 94 17 100 93 79 18 (1) 100 89 97 18 (4) 100 53 83 18 (8) 100 86 86 18 (17) 100 92 83 18 (18) 100 87 78 18 (19) 100 100  98 20 (1)  30 72 98 20 (2) 100 93 92 21  30 28 74 29 100 92 110  40 100 91 108  41 (2) 100 94 71 41 (3) 100 80 97 41 (4) 100 96 82 41 (5) 100 94 90 41 (6) 100 49 97 41 (7)  70 87 71 41 (8)  50 53 78 41 (9)  70 53 95 41 (10)  50 73 75 41 (11) 100 90 85 41 (12) 100 87 79 41 (13)  40 56 77 41 (14) 100 92 73 41 (15)  30 86 100  44  30 62 75 47  30 47 83 B-9 100 46 89 B-13  10 24 98

The compounds of Example No. 1, 6(3), 6(5), 13, 15, 17, 18(1), 18(8), 20(1) and 20(2) were converted to sodium salts according to the method of Example 42, and then used for the assay.

Test Example 4: Type II Collagen-induced Arthritis in Mice

The compound of Example 20 (1) was tested for the effect on type II collagen-induced arthritis, using 8 weeks old, male DBA/1J mice (Japan Charles River). Emulsion was prepared by mixing an equal volume of bovine type II collagen (prepared by Koken) in 0.1N acetic acid (2 mg/ml) and Freund's complete adjuvant (prepared by Nacalai Tesque). Arthritis was induced by intradermal injection of 0.2 ml (the quantity of antigen: 200 μg/head) of the emulsion into the skin of the tail root twice (day 0 and day 21). The test compound was suspended in 0.5% solution of methyl cellulose, and 100 mg/kg was orally administered once every day from day 21 to day 35. To the control group (negative control group), 0.5% methyl cellulose solution was administered in the same manner as above. Severity of the arthritis was scored 0: no change, 1: only one or two swelling of the joints or slight swelling of the ankle or toes, 2: swelling and/or rubor in further joints, 3: extensive swelling of whole paw, and the maximum possible score for arthritis was 12 points. As to the severity of destruction of joints and bones, X ray photographs of four paws were taken (Softex), and severity of destruction in the second to fifth articulationes interphalangeae, first to fifth articulationes metacarpophalangeae and metatarsophalangeae, and calcaneus was scored by 0 or 1 in accordance with presence or absence of destruction, and the severity of destruction in the carpus and tarsal was scored by 0 to 3. Overall severity of destruction of joints and bones was evaluated by a joint-bone destruction score, taking the total score of the four paws as 50 points [Method in Enzymology, 162, 361-373 (1988)].

The results are shown in Table 53, wherein the scores are mean values.

TABLE 53 Example Dosage Arthritis Joint-bone No. (mg/kg) score destruction score Control — 10 ± 1 20 ± 3 20 (1) 100  8 ± 1 14 ± 3

BEST EMBODIMENT FOR CARRYING OUT THE INVENTION

Next, the present invention is explained by referring to referential examples and examples. The present invention is by no means limited by these examples. In the paragraphs of eluents, all the mixing ratios are expressed by volume. The carrier used in the column chromatography is Silica Gel 60, No. 7734 (product of Merck).

Amino acid residues are expressed according to the three-letter system prescribed by IUPAC and IUB. Unless otherwise referred to, meanings of the abbreviations are as follows:

Fmoc: 9-Fluorenylmethoxycarbonyl

PyBOP: Benzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate

HOBt: N-Hydroxybenzotriazole

DMF: N,N-Dimethylformamide

DIEA: N,N-Diisopropylethylamine

DCM: Dichloromethane

TFA: Trifluoroacetic acid

DIPCDI: Diisopropyl carbodiimide

PMC: 2,2,5,7,8-Pentamethylchroman-6-sulfonyl

DMSO: Dimethyl sulfoxide

Ac: Acetyl

Py: Pyridyl

Cit: Citrolline

EXAMPLE 1

To 20 ml of toluene were added 1.90 g of 4-(3-methylbutylidene)-1-cyclohexanone and 2.05 g of benzyl 3-aminopropionate, and the mixture was stirred at ambient temperature for one hour. Then, 1.72 g of mercaptosuccinic acid was added, and the resulting mixture was heated under reflux for one hour under the condition of azeotropic dehydration by means of Dean Stark. The reaction mixture was added to a mixture of ice water and ethyl acetate, pH was adjusted to 2.0 with 2 mol/L hydrochloric acid, and the organic layer was separated. The organic layer was washed successively with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue thus obtained was purified by column chromatography [eluent: chloroform:ethanol=50:1] to obtain 3.10 g of 2-[4-[3-(benzyloxy)-3-oxopropyl]-8-(3-methylbutylidene)-3-oxo-1-thia-4-azaspiro[4.5]decan-2-yl]-acetic acid as a light yellow oily product.

NMR (CDCl₃+D₂O) δ: 0.89(6H,d,J=6.4 Hz), 1.4-2.9(14H,m), 3.19(1H,dd,J=5.2 Hz,17.0 Hz), 3.4-3.7(2H,m), 4.14(lH,dd,J=5.2 Hz,8.1 Hz), 5.0-5.4(1H,m), 5.12(2H,s), 7.35(5H,s)

EXAMPLE 2

The procedure of Example 1 was repeated to obtain the following compound:

2-[8-(3-methylbutylidene)-3-oxo-4-(5-phenylpentyl)-1-thia-4-azaspiro[4.5]decan-2-yl]-acetic acid

NMR (CDCl₃) δ: 0.88(6H,d,J=6.1 Hz), 1.1-3.4(23H,m), 4.1-4.3(1H,m), 5.1-5.3(1H,m), 7.21(5H,s), 8.5-9.3(1H,bs)

EXAMPLE 3

To 8 ml of toluene were added 0.75 g of 4-(3-methylbutylidene)-1-cyclohexanone and 0.89 g of benzyl 3-aminopropionate, and the mixture was stirred at ambient temperature for one hour. Then, 1.02 g of β-tert-butyl 2-mercaptosuccinate was added, and the resulting mixture was heated under reflux for 8 hours under the condition of azeotropic dehydration by means of Dean Stark apparatus. The reaction mixture was poured into a mixture of ice water and ethyl acetate, pH was adjusted to 2.0 with 2 mol/L hydrochloric acid, and the organic layer was separated. The organic layer was washed successively with water, saturated aqueous solution of sodium hydrogen carbonate and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue thus obtained was purified by column chromatography [eluent: hexane:ethyl acetate=6:1] to obtain 0.75 g of benzyl 3-[2-[2-(tert-butoxy)-2-oxoethyl-8-(3-methylbutylidene)-3-oxo-1-thia-4-azaspiro[4.5]decan-4-yl]-propionate as a light yellow oily product.

NMR (CDCl₃) δ: 0.88(6H,d,J=6.4 Hz), 1.4-2.9(14H,m), 1.46(9H,s), 3.15(1H,dd,J=3.8 Hz, 16.7 Hz), 3.4-3.7(2H,m), 4.08(1H,dd,J=3.8 Hz,9.9 Hz), 5.1-5.3(1H,m), 5.11(2H,s), 7.35(5H,s)

EXAMPLE 4

The procedure of Example 3 was repeated to obtain the compounds of Tables 54 and 55.

TABLE 54

No. A R² 4 (1)

4 (2)

4 (3)

4 (4)

4 (5)

4 (6)

4 (7)

TABLE 55 No. A R² 4 (8)

4 (9)

4 (10)

4 (11)

4 (12)

4 (13)

4 (14)

—CH₂CH₂CH₃ 4 (15)

—CH₂CH₂OCH₃

Properties of the compounds of Tables 54 and 55 are shown below.

4(1)

NMR(CDCl₃) δ: 0.89 (6H,d,J=6.3 Hz), 1.3-3.7 (17H,m), 1.48 (9H,s), 4.13 (1H,dd,J=3.7 Hz,10.3 Hz), 5.19 (1H,t,J=7.1 Hz), 7.26 (5H,s)

4(2)

NMR(CDCl₃) δ: 0.87 (6H,d,J=6.1 Hz), 1.2-2.8 (12H,m), 1.48 (9H,s), 3.24 (1H,dd,J=3.8 Hz,16.7 Hz), 4.22 (1H,dd,J=3.8 Hz,9.9 Hz), 4.42 (1H,d,J=15.5 Hz), 4.68 (1H,d,J=15.5 Hz), 5.1-5.3 (1H,m), 7.1-7.4 (1H,m), 7.5-7.8 (1H,m), 8.3-8.7 (2H,m)

4(3)

NMR(CDCl₃) δ: 0.91 (6H,d,J=6.1 Hz), 1.2-3.6 (13H,m), 1.48 (9H,s), 4.33 (1H,dd,J=3.9 Hz,9.3 Hz), 5.1-5.5 (1H,m), 7.06 (1H,d,J=3.5 Hz), 7.50 (1H,d,J=3.5 Hz)

4(4)

NMR(CDCl₃) δ: 0.7-1.0 (6H,m), 1.46 (9H,s), 1.5-3.0 (12H,m), 3.1-3.5 (1H,m), 3.73 (3H,s), 4.0-4.3 (1H,m), 4.84 (1H,bs), 5.0-5.3 (1H,m), 7.34 (5H,s)

4(5)

NMR(CDCl₃) δ: 1.23 (6H,d,J=6.8 Hz), 1.46 (9H,s), 1.4-3.0 (12H,m), 3.16 (1H,dd,J=3.7,16.7 Hz), 3.5-3.8 (2H,m), 4.07 (1H,dd,J=3.7 Hz,10.3 Hz), 4.6-4.8 (1H,m), 5.13 (2H,s), 6.83 (2H,d,J=8.7 Hz), 7.14 (2H,d,J=8.7 Hz), 7.35 (5H,s)

4(6)

NMR(CDCl₃) δ: 1.22 (6H,d,J=6.8 Hz), 1.47 (9H,s), 1.5-2.3 (8H,m), 2.4-3.1 (5H,m), 3.2-3.5 (2H,m), 3.9-4.2 (2H,m), 6.81 (2H,d,J=8.6 Hz), 7.13 (2H,d,J=8.6 Hz), 7.27 (5H,s)

4(7)

NMR(CDCl₃) δ: 1.46 (9H,s), 1.4-2.9 (11H,m), 3.17 (1H,dd,J=3.7 Hz,16.6 Hz), 3.5-3.8 (2H,m), 4.08 (1H,dd,J=3.7 Hz,10.0 Hz), 4.4-4.6 (1H,m), 5.14 (2H,s), 6.8-7.6 (10H,m)

4(8)

NMR(CDCl₃) δ: 1.46 (9H,s), 1.67 (6H,s), 1.6-2.8(11H,m), 3.15 (H,dd,J=3.8 Hz,16.6 Hz), 3.4-3.7 (2H,m), 4.08 (1H,dd,J=3.8 Hz,10.0 Hz), 5.12 (2H,s), 7.34 (5H,s)

4(9)

NMR(CDCl₃) δ: 1.46 (9H,s), 1.58 (3H,d,J=6.8 Hz), 1.7-2.8 (11H,m), 3.15 (1H,dd,J=3.8 Hz,16.7 Hz), 3.4-3.7 (2H,m), 4.08 (1H,dd,J=3.8 Hz,9.9 Hz), 5.11 (2H,s), 5.1-5.3 (1H,m), 7.35 (5H,s)

4(10)

NMR(CDCl₃) δ: 0.91 (6H,d,J=6.4 Hz), 1.2-2.8 (15H,m), 1.46 (9H,s), 3.0-3.3 (3H,m), 3.4-3.7 (2H,m), 4.02 (1H,dd,J=3.7 Hz,10.0 Hz), 5.12 (2H,s), 5.5-5.8 (1H,m), 7.36 (5H,s)

4(11)

NMR(CDCl₃) δ: 0.8-1.0 (6H,m), 1.2-2.8 (18H,m), 1.46 (9H,s), 3.0-3.7 (7H,m), 4.03 (1H,dd,J=3.7 Hz,10.3 Hz), 5.12 (2H,s), 7.36 (5H,s)

4(12)

NMR(CDCl₃) δ: 0.76 (6H,t,J=7.3 Hz), 1.1-2.9 (15H,m), 1.46 (9H,s), 3.13 (1H,dd,J=3.7 Hz,16.6 Hz), 3.5-3.8 (2H,m), 4.03 (1H,dd,J=3.7 Hz,10.0 Hz), 5.13 (2H,s), 7.36 (5H,s)

4(13)

NMR(CDCl₃) δ: 0.76 (6H,t,J=7.3 Hz), 1.1-2.3 (12H,m), 1.47 (9H,s), 2.52 (1H,dd,J=10.3 Hz,16.6 Hz), 2.8-3.7 (5H,m), 4.08 (1H,dd,J=3.7 Hz,10.3 Hz), 7.27 (5H,m)

EXAMPLE 5

In 10 ml of methylene chloride was dissolved 0.50 g of benzyl 3-[2-[2-(tert-butoxy)-2-oxoethyl]-8-(3-methylbutylidene)-3-oxo-1-thia-4-azaspiro[4.5]decan-4-yl]-propionate. After adding 2 ml of trifluoroacetic acid at 0-5° C., the mixture was stirred at ambient temperature of 2 hours. Distillation of the solvent under reduced pressure, followed by an azeotropic distillation with toluene gave 0.37 g of 2-[4-[3-(benzyloxy)-3-oxopropyl]-8-(3-methylbuthylidene)-3-oxo-1-thia-4-azaspiro[4.5]decan-2-yl]-acetic acid as a light yellow oily product.

NMR (CDCl₃+D₂O) δ: 0.89(6H,d,J=6.4 Hz), 1.4-2.9(14H,m), 3.19 (1H,dd,J=5.2 Hz,17.0 Hz), 3.4-3.7(2H,m), 4.14(1H,dd,J=5.2 Hz, 8.1 Hz), 5.0-5.4(1H,m), 5.12(2H,s), 7.35(5H,s)

EXAMPLE 6

The procedure of Example 5 was repeated to obtain the compounds of Tables 56 and 57.

TABLE 56

No. A R² 6 (1)

6 (2)

6 (3)

6 (4)

6 (5)

6 (6)

6 (7)

TABLE 57 No. A R² 6 (8)

6 (9)

6 (10)

6 (11)

6 (12)

6 (13)

6 (14)

—CH₂CH₂CH₃ 6 (15)

—CH₂CH₂OCH₃

Properties of the compounds of Tables 56 and 57 are shown below.

6(1)

NMR(CDCl₃) δ: 0.89 (6H,d,J=6.1 Hz), 1.3-3.7 (17H,m), 4.20 (1H,dd,J=4.6 Hz,8.5 Hz), 5.20 (1H,t,J=7.2 Hz), 7.26 (5H,s), 8.8-9.2 (1H,bs)

6(2)

NMR(CDCl₃) δ: 0.85 (6H,d,J=6.1 Hz), 1.2-3.4 (13H,m), 4.1-5.6 (4H,m), 7.8-9.2 (4H,m), 11.5-12.4 (1H,bs)

6(3)

NMR(CDCl₃) δ: 0.91 (6H,d,J=5.4 Hz), 1.2-3.6 (13H,m), 4.39 (1H,dd,J=4.4 Hz,8.8 Hz), 5.1-5.4 (1H,m), 7.09 (1H,d,J=3.7 Hz), 7.52 (1H,d,J=3.7 Hz), 6.1-7.0 (1H,bs)

6(4)

NMR(CDCl₃) δ: 0.87 (6H,d,J=6.1 Hz), 1.1-3.0 (12H,m), 3.1-3.5 (1H,m), 3.75 (3H,s), 4.1-4.4 (1H,m), 5.1-5.7 (2H,m), 4.85 (1H,bs), 7.34 (5H,s)

6(5)

NMR(CDCl₃) δ: 1.23 (6H,d,J=6.8 Hz), 1.4-3.0 (12H,m), 3.23 (1H,dd,J=4.6 Hz,17.3 Hz), 3.5-3.8 (2H,m), 4.13 (1H,dd,J=4.6 Hz,8.8 Hz), 4.3-4.6(1H,m), 5.14 (2H,s), 6.83 (2H,d,J=8.7 Hz), 7.14 (2H,d,J=8.7 Hz), 7.35 (5H,s), 8.6-9.4 (1H,bs)

6(6)

NMR(CDCl₃) δ: 1.22 (6H,d,J=6.8 Hz), 1.6-2.3 (8H,m), 2.6-3.7 (7H,m), 3.9-4.3 (2H,m), 6.81 (2H, d,J=8.6 Hz), 7.13 (2H,d,J=8.6 Hz), 7.27 (5H,s), 7.1-7.4 (1H,bs)

6(7)

NMR(CDCl₃+D₂O) δ: 1.4-2.9 (11H,m), 3.21 (1H,dd,J=4.6 Hz,17.1 Hz), 3.5-3.8 (2H,m), 4.12 (1H,dd,J=4.6 Hz,8.4 Hz), 4.4-4.6 (1H,m), 5.14 (2H,s), 6.8-7.6 (10H,m)

6(8)

NMR(CDCl₃) δ: 1.54 (6H,s), 1.6-2.2 (8H,m), 2.6-2.9 (3H,m), 3.21 (1H,dd,J=4.5 Hz,17.2 Hz), 3.5-3.7 (2H,m), 4.11 (1H,dd,J=4.5 Hz,8.5 Hz), 5.13 (2H,s), 7.36 (5H,s), 8.0-8.6 (1H,bs)

6(9)

NMR(CDCl₃) δ: 1.59 (3H,d,J=6.6 Hz), 1.5-2.9 (11H,m), 3.21 (1H,dd,J=5.0 Hz,17.0 Hz), 3.4-3.7 (2H,m), 4.14 (1H,dd,J=5.0 Hz,8.1 Hz), 5.12 (2H,s), 5.1-5.4 (1H,m), 6.6-7.0 (1H,bs), 7.35 (5H,m)

6(10)

NMR(CDCl₃) δ: 0.91 (6H,d,J=6.6 Hz), 1.2-2.3 (12H,m), 2.5-2.9 (3H,m), 3.0-3.8 (5H,m), 4.09 (1H,dd,J=4.0 Hz,8.9 Hz), 5.13 (2H,s), 5.7-6.0 (1H,m), 6.3-6.7 (1H,bs), 7.35 (5H,s)

6(11)

NMR(CDCl₃) δ: 0.8-1.0 (6H,m), 1.2-2.9 (18H,m), 3.0-3.7 (7H,m), 4.09 (1H,dd,J=4.4 Hz,8.6 Hz), 4.4-4.8 (1H,bs), 5.12 (2H,s), 7.35 (5H,s)

6(12)

NMR(CDCl₃+D₂O) δ: 0.76 (6H,t,J=7.3 Hz), 1.1-2.3 (12H,m), 2.3-2.9 (3H,m), 3.19 (1H,dd,J=5.1 Hz,17.0 Hz), 3.5-3.8 (2H,m), 4.09 (1H,dd,J=5.1 Hz,8.3 Hz), 5.14 (2H,s), 7.36 (5H,s)

6(13)

NMR(CDCl₃+D₂O) δ: 0.76 (6H,t,J=7.4 Hz), 1.1-2.3 (12H,m), 2.5-3.7 (6H,m), 4.16 (1H,dd,J=5.3 Hz,8.4 Hz), 7.26 (5H,s)

6(14)

NMR(CDCl₃+D₂O) δ: 0.8-1.2 (9H,m), 1.2-3.4 (17H,m), 4.17 (1H,dd,J=4.2 Hz,9.0 Hz), 5.1-5.4 (1H,m)

6(15)

NMR(CDCl₃) δ: 0.88 (6H,d,J=6.1 Hz), 1.2-3.7 (17H,m), 3.34 (3H,s), 4.17 (1H,dd,J=5.3 Hz,8.2 Hz), 5.1-5.3 (1H,m), 7.8-8.2 (1H,bs)

EXAMPLE 7

In an atmosphere of nitrogen, 3.32 g of 4-(3-methylbutylidene)-1-cyclohexanone and 5.35 g of benzyl 3-aminopropionate were added to 35 ml of dioxane and stirred at ambient temperature for 30 minutes, after which 2.25 g of mercaptoacetic acid was added and the resulting mixture was stirred under reflux for 3 hours. The reaction mixture was poured into a mixture of ice water and ethyl acetate, pH was adjusted to 2.0 with 2 mol/L hydrochloric acid, and the organic layer was separated. The organic layer was washed successively with water, saturated aqueous solution of sodium hydrogen carbonate and saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification of the residue by column chromatography (eluent: hexane:ethyl acetate=6:1) gave 4.36 g of benzyl 3-[8-(3-methylbutylidene)-3-oxo-1-thia-4-azaspiro[4.5]decan-4-yl]-propionate as a light yellow oily product.

NMR (CDCl₃) δ: 0.88(6H,d,J=6.1 Hz), 1.4-2.8(13H,m), 3.4-3.7 (2H,m), 3.51 (2H,s), 5.1-5.3(1H,m), 5.12(2H,s), 7.35(5H,s)

EXAMPLE 8

In 40 ml of dioxane was dissolved 4.11 g of benzyl 3-[8-(3-methylbutylidene)-3-oxo-1-thia-4-azaspiro[4.5]decan-4-yl]-propionate. Then, 20.5 ml of 1 mol/L aqueous solution of sodium hydroxide was added at 0-5° C., and the resulting mixture was stirred at ambient temperature for one hour. The reaction mixture was poured into a mixture of chloroform and water, the aqueous layer was separated, ethyl acetate was added to the aqueous layer, pH was adjusted to 2.0 with 2 mol/L hydrochloric acid, and the organic layer was separated. The organic layer was washed successively with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification of the residue by column chromatography (eluent: chloroform:ethanol=50:1) gave 2.72 g of 3-[8-(3-methylbutylidene)-3-oxo-1-thia-4-azaspiro[4.5]decan-4-yl]-propionic acid as a light yellow oily product.

NMR (CDCl₃) δ: 0.88(6H,d,J=6.4 Hz), 1.4-2.8(13H,m), 3.4-3.7 (2H,m), 3.56(2H,s), 5.1-5.3(1H,m), 7.4-8.1(1H,bs)

EXAMPLE 9

In an atmosphere of nitrogen, 1.97 ml of N,N-diisopropylamine was added to 10 ml of anhydrous tetrahydrofuran, to which was dropwise added 9.50 ml of a solution of n-butyllithium in hexane (1.58 mol/L) at −30° C. The mixture was stirred at the same temperature for 10 minutes and then cooled to −70° C., to which was dropwise added a solution of 1.56 g of 3-[8-(3-methylbutylidene)-3-oxo-1-thia-4-azaspiro[4.5]decan-4-yl]-propionic acid in 20 ml of anhydrous tetrahydrofuran. After stirring the resulting mixture at the same temperature as above for 30 minutes, 0.89 ml of tert-butyl bromoacetate was dropwise added at the same temperature. After elevating the temperature to 0° C., the reaction mixture was poured into a mixture of ice water and ethyl acetate, pH was adjusted to 2.0 with 2 mol/L hydrochloric acid, and the organic layer was separated. The organic layer was washed successively with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Thus, 2.23 g of 3-[2-[2-(tert-butoxy)-2-oxoethyl]-8-(3-methylbutylidene)-3-oxo-1-thia-4-azaspiro[4.5]decan-4-yl]-propionic acid was obtained as a yellow oily product.

NMR (CDCl₃) δ: 0.87(6H,d,J=6.3 Hz), 1.2-2.8(14H,m), 1.46(9H,s), 3.13(1H,dd,J=3.9 Hz,16.6 Hz), 3.4-3.7(2H,m), 4.11 (1H,dd,J=3.9 Hz,9.6 Hz), 5.1-5.3(1H,m), 6.8-7.6(1H,bs)

EXAMPLE 10

In 10 ml of methylene chloride was dissolved 0.56 g of 3-[2-[2-(tert-butoxy)-2-oxoethyl]-8-(3-methylbutylidene)-3-oxo-1-thia-4-azaspiro[4.5]decan-4-yl]-propionic acid. At ambient temperature, 0.21 g of benzyl alcohol, 0.23 g of 1-hydroxybenzotriazole monohydrate and 0.31 g of dicyclohexyl carbodiimide were successively added. After stirring the resulting mixture for 24 hours at the same temperature as above, the insoluble matter was filtered off. The filtrate was washed successively with 2 mol/L hydrochloric acid, water, saturated aqueous solution of sodium hydrogen carbonate and saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. Purification of the residue by column chromatography [eluent: hexane:ethyl acetate=6:1] gave 0.17 g of benzyl 3-[2-[2-(tert-butoxy)-2-oxoethyl]-8-(3-methylbutylidene)-3-oxo-1-thia-4-azaspiro[4.5]decan-4-yl]-propionate as a light yellow oily product.

NMR (CDCl₃) δ: 0.88(6H,d,J=6.4 Hz), 1.4-2.9(14H,m), 1.46(9H,s), 3.15(1H,dd,J=3.8 Hz,16.7 Hz), 3.4-3.7(2H,m), 4.08(1H,dd,J=3.8 Hz,9.9 Hz), 5.1-5.3(1H,m), 5.11(2H,s), 7.35(5H,s)

EXAMPLE 11

In 7 ml of N,N-dimethylformamide was added 0.70 g of 3-[2-[2-(tert-butoxy)-2-oxoethyl]-8-(3-methylbutylidene)-3-oxo-1-thia-4-azaspiro[4.5]decan-4-yl]-propionic acid. After adding 0.14 ml of ethyl iodide and 0.25 g of anhydrous potassium carbonate at 0-5° C., the resulting mixture was stirred at ambient temperature for 3 hours. The resulting mixture was poured into a mixture of ice water and ethyl acetate, pH was adjusted to 2.0 with 2 mol/L hydrochloric acid, and the organic layer was separated. The organic layer was washed successively with water, saturated aqueous solution of sodium hydrogen carbonate and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Thus, 0.70 g of ethyl 3-[2-[2-(tert-butoxy)-2-oxoethyl]-8-(3-methylbutylidene)-3-oxo-1-thia-4-azaspiro[4.5]decan-4-yl]-propionate was obtained as a light yellow oily product.

NMR (CDCl₃) δ: 0.88(6H,d,J=6.1 Hz), 1.25(3H,t,J=7.1 Hz), 1.46(9H,s), 1.6-2.8(14H,m), 3.15(1H,dd,J=3.9 Hz,16.6 Hz), 3.4-3.7(2H,m), 3.9-4.2(1H,m), 4.13(2H,q,J=7.1 Hz), 5.1-5.3(1H,m)

EXAMPLE 12

The procedure of Example 11 was repeated to obtain benzyl 3-[2-[2-(methoxy-2-oxoethyl)-8-(3-methylbutylidene)-3-oxo-1-thia-4-azaspiro[4.5]decan-4-yl]-propionate.

NMR (CDCl₃) δ: 0.87(6H,d,J=6.1 Hz), 1.4-2.8(14H,m), 3.19 (1H,dd,J=3.9 Hz,16.8 Hz), 3.4-3.8(2H,m), 3.71(3H,s), 4.12 (1H,dd,J=3.9 Hz,9.4 Hz), 5.11(2H,s), 5.1-5.3(1H,m), 7.34(5H,s)

EXAMPLE 13

The procedure of Example 5 was repeated to obtain 2-[4-[3-(ethoxy-3-oxopropyl)-8-(3-methylbutylidene)-3-oxo-1-thia-4-azaspiro[4.5]decan-2-yl]-acetic acid.

NMR (CDCl₃) δ: 0.88(6H,d,J=5.4 Hz), 1.26(3H,t,J=7.1 Hz), 1.4-3.8(17H,m), 4.15(2H,q,J=7.1 Hz), 4.0-4.3(1H,m), 5.1-5.3(1H,m), 10.2(1H,bs)

EXAMPLE 14

In 10 ml of methylene chloride was dissolved 0.96 g of 2-[4-[3-(benzyloxy)-3-oxopropyl]-8-(3-methylbutylidene)-3-oxo-1-thia-4-azaspiro[4.5]decan-2-yl]-acetic acid. After adding 0.18 ml of thionyl chloride at ambient temperature, the resulting mixture was stirred for one hour under reflux. The reaction mixture was concentrated under reduced pressure, and the concentrate was dissolved in 10 ml of dioxane. The resulting solution was dropwise added at 0-5° C. to an ethyl ether solution containing diazomethane prepared from 5.00 g of N-methylnitrosourea, 3.00 g of potassium hydroxide, 4.00 ml of water and 15 ml of ethyl ether, and the resulting mixture was stirred at ambient temperature for 30 minutes. The reaction mixture was poured into a mixture of water, acetic acid and ethyl acetate, and the organic layer was separated. The organic layer thus obtained was washed successively with water, saturated aqueous solution of sodium hydrogen carbonate and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in a mixture of 10 ml dioxane and 10 ml water, and the resulting solution was added to a mixture of 0.16 g of silver benzoate and 3.00 ml of triethylamine at ambient temperature and stirred for 2 hours. The reaction mixture was poured into a mixture of water and ethyl acetate, pH was adjusted to 2.0 with 2 mol/L hydrochloric acid, and the organic layer was separated. The organic layer thus obtained was washed successively with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification of the residue by column chromatography [eluent: chloroform:ethanol=80:1] gave 0.36 g of 3-[4-[3-(benzyloxy)-3-oxopropyl]-8-(3-methylbutylidene)-3-oxo-1-thia-4-azaspiro[4.5]decan-2-yl]-propionic acid as a light yellow oily product.

NMR (CDCl₃) δ: 0.89(6H,d,J=6.1 Hz), 1.4-2.8(17H,m), 3.4-3.7 (2H,m), 3.8-4.0(1H,m), 5.12(2H,s), 5.1-5.3(1H,m), 7.35(5H,s), 8.1-8.9(1H,bs)

EXAMPLE 15

In a solvent mixture consisting of 21 ml of ethanol and 9 ml of water were dissolved 3.10 g of 4-(4-isopropylphenoxy)-1-cyclohexanone, 2.35 g of L-cysteine hydrochloride monohydrate and 1.10 g of sodium acetate. The mixture was stirred at ambient temperature for 6 hours. The reaction mixture was concentrated under reduced pressure, and water and ethyl ether were added to the concentrate. The deposited crystal was collected by filtration, and there was obtained 2.45 g of (3R)-8-(4-isopropylphenoxy)-1-thia-4-azaspiro[4.5]decan-3-carboxylic acid as a colorless crystalline product.

NMR (d₆-DMSO+D₂O) δ: 1.17(6H,d,J=6.8 Hz), 1.3-2.3(8H,m), 2.6-3.4(3H,m), 3.8-4.2(1H,m), 4.2-4.6(1H,m), 6.85(2H,d,J=8.5 Hz), 7.13(2H,d,J=8.5 Hz)

EXAMPLE 16

The procedure of Example 15 was repeated to obtain the compound listed in Tables 58 to 60.

TABLE 58

No. A R¹ 16(1)

16(2)

16(3)

16(4)

16(5)

16(6)

TABLE 59 No. A R³ 16 (7)

16 (8)

16 (9)

16 (10)

16 (11)

16 (12)

16 (13)

TABLE 60 No. A R¹³ 16 (14)

16 (15)

16 (16)

16 (17)

Properties of the compounds shown in Tables 58-60 are as follows.

16(1)

NMR(d₆-DMSO+D₂O) δ: 1.16 (6H,d,J=6.8 Hz), 1.3-2.3 (8H,m), 2.6-3.0 (2H,m), 3.1-3.4 (1H,m), 3.9-4.2 (1H,m), 4.2-4.6 (1H,m), 6.85 (2H,d,J=8.5 Hz), 7.13 (2H,d,J=8.5 Hz)

16(2)

NMR(d₆-DMSO+D₂O) δ: 1.3-2.3 (8H,m), 2.7-3.0 (1H,m), 3.1-3.4 (1H,m), 3.81 (3H,s), 3.9-4.7 (2H,m), 7.06 (2H,d,J=8.7 Hz), 7.89 (2H,d,J=8.7 Hz)

16(3)

NMR(d₆-DMSO) δ: 1.3-2.3 (8H,m), 2.7-3.0 (1H,m), 3.1-3.4 (1H,m), 3.69 (3H,s), 3.9-4.1 (1H,m), 4.2-4.5 (1H,m), 4.6-5.6 (2H,bs), 6.8-7.0 (4H,m)

16(4)

NMR(d₆-DMSO) δ: 1.3-2.3 (8H,m), 2.42 (3H,s), 2.7-3.0 (1H,m), 3.1-3.4 (1H,m), 3.9-4.1 (1H,m), 4.2-4.6 (1H,m), 4.8-6.2 (2H,bs), 6.92 (2H,d,J=8.7 Hz), 7.23 (2H,d, J=8.7 Hz)

16(5)

NMR(d₆-DMSO) δ: 1.4-2.4 (8H,m), 2.7-3.0 (1H,m), 3.1-3.4 (1H,m), 3.15 (3H,s), 3.9-4.1 (1H,m), 4.3-5.2 (3H,m), 7.18 (2H,d,J=8.7 Hz), 7.82 (2H,d,J=8.7 Hz)

16(6)

NMR(d₆-DMSO) δ: 1.17 (3H,t,J=7.1 Hz), 1.4-2.5 (9H,m), 2.7-3.0 (1H,m), 3.1-3.4 (1H,m), 3.8-4.3 (1H,m), 5.2-7.2 (2H,bs), 4.05 (2H,q,J=7.1 Hz)

16(7)

NMR(d₆-DMSO) δ: 1.27 (9H,s), 1.5-2.4 (8H,m), 2.7-3.0 (1H,m), 3.1-3.4 (1H,m), 3.9-4.2 (1H,m), 4.4-6.4 (3H,bs),7.35 (4H,s)

16(11)

NMR(CDCl₃) δ: 0.87 (6H,d,J=6.4 Hz), 1.2-2.8 (11H,m), 3.1-3.6 (2H,m), 4.35 (1H,t,J=7.6 Hz), 5.19 (1H,t,J=7.3 Hz), 7.7-8.2 (2H,m)

16(13)

NMR(CDCl₃) δ: 0.87 (6H,d,J=6.1 Hz), 1.2-2.8 (11H,m), 3.1-3.6 (2H,m), 4.34 (1H,t,J=7.8 Hz), 5.19 (1H,t,J=7.1 Hz), 6.9-7.5 (2H,m)

16(14)

NMR(d₆-DMSO) δ: 1.5-2.4 (10H,m), 2.7-3.0 (5H,m), 3.2-3.6 (1H,m), 3.9-4.6 (2H,m), 5.07 (2H,bs), 6.6-6.9 (2H,m), 7.0-7.2 (1H,m)

16(15)

NMR(CDCl₃) δ: 0.6-2.8 (15H,m), 3.1-3.6 (2H,m), 4.35 (1H,dd,J=6.8 Hz,7.6 Hz), 5.18 (1H,t,J=7.6 Hz), 7.87 (1H,bs)

16(16)

NMR(d₆-DMSO) δ: 0.89 (6H,d,J=5.9 Hz), 1.5-3.5 (11H,m), 3.8-4.2 (1H,m), 4.8-5.2 (1H,m)

16(17)

NMR(CDCl₃) δ: 0.89 (6H,d,J=6.3 Hz), 1.0-2.8 (13H,m), 3.1-3.7 (2H,m), 4.2-4.5 (1H,m), 5.12 (1H,t,J=3.5 Hz), 6.36 (2H,bs)

EXAMPLE 17

In 50 ml of methylene chloride were dissolved 2.40 g of (3R)-8-(4-isopropylphenoxy)-1-thia-4-azaspiro[4.5]decan-3-carboxylic acid and 2.23 ml of triethylamine. To the solution thus obtained was dropwise added 1.41 g of benzoyl chloride at 0-5° C., and the resulting mixture was stirred at the same temperature as above for 3 hours. The reaction mixture was poured into ice water, pH was adjusted to 1.0 with 2 mol/L hydrochloric acid, and the organic layer was separated. The organic layer thus obtained was washed successively with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Ethyl ether was added to the residue thus obtained, and the deposited crystal was collected by filtration. Thus, 2.10 g of (3R)-4-benzoyl-8-(4-isopropylphenoxy)-1-thia-4-azaspiro[4.5]decan-3-carboxylic acid was obtained as a colorless crystalline product.

NMR (d₆-DMSO+D₂O) δ: 1.17(6H,d,J=6.8 Hz), 1.3-2.3(6H,m), 2.6-3.7(5H,m), 4.4-4.6(1H,m), 4.7-4.9(1H,m), 6.87(2H,d,J=8.6 Hz), 7.15(2H,d,J=8.6 Hz), 7.2-7.5(5H,m)

EXAMPLE 18

The procedure of Example 17 was repeated to obtain the compounds listed in Tables 61 to 63.

TABLE 61

No. A R^(2b) R³ 18 (1)

18 (2)

18 (3)

18 (4)

18 (5)

18 (6)

18 (7)

TABLE 62 No. A R^(2b) R³ 18 (8)

18 (9)

—CH₃

18 (10)

18 (11)

18 (12)

—CH₂CH₂COOEt

18 (13)

18 (14)

18 (15)

18 (16)

TABLE 63 No. A R^(2b) R³ 18 (17)

18 (18)

18 (19)

Properties of the compounds of Tables 61-63 are as follows.

18(1)

NMR(d₆-DMSO) δ: 1.17 (6H,d,J=6.8 Hz), 1.3-2.3 (6H,m), 2.6-3.7 (5H,m), 4.4-4.6 (1H,m), 4.7-4.9 (1H,m), 6.87 (2H,d,J=8.6 Hz), 7.15 (2H,d,J=8.6 Hz), 7.2-7.6 (6H,m)

18(2)

NMR(d₆-DMSO+D₂O) δ: 1.4-2.4 (6H,m), 3.0-3.7 (4H,m), 3.82 (3H,s), 4.6-4.9 (2H,m), 7.06 (2H,d,J=8.4 Hz), 7.40 (5H,s), 7.93 (2H,d,J=8.4 Hz)

18(3)

NMR(d₆-DMSO+D₂O) δ: 1.3-2.3 (6H,m), 2.9-3.6 (4H,m), 3.69 (3H,s), 4.3-4.6 (1H,m), 4.7-4.9 (1H,m), 6.7-7.0 (4H,m), 7.2-7.6 (5H,m)

18(4)

NMR(d₆-DMSO+D₂O) δ: 1.3-2.3 (6H,m), 2.42 (3H,s), 2.9-3.7 (4H,m), 4.4-4.7 (1H,m), 4.7-4.9 (1H,m), 6.94 (2H,d,J=8.7 Hz), 7.25 (2H,d,J=8.7 Hz), 7.39 (5H,s)

18(5)

NMR(d₆-DMSO+D₂O) δ: 1.3-2.3 (6H,m), 2.8-3.7 (4H,m), 3.16 (3H,s),4.6-4.9 (2H,m), 7.17 (2H,d,J=8.7 Hz), 7.40 (5H,s), 7.86 (2H,d,J=8.7 Hz)

18(6)

NMR(CDCl₃) δ: 1.4-3.8 (15H,m), 4.6-4.9 (1H,m), 5.10 (2H,s), 6.7-7.1 (1H,m), 7.2-7.5 (10H,m), 8.93 (1H,bs)

18(7)

NMR(d₆-DMSO) δ: 1.28 (9H,s), 1.5-2.4 (6H,m), 2.9-3.8 (5H,m), 4.6-5.0 (2H,m), 7.37 (9H,s)

18(8)

NMR(CDCl₃+D₂O) δ: 0.89 (6H,d,J=5.9 Hz), 1.4-3.4 (13H,m), 4.7-4.9 (1H,m), 5.1-5.3 (1H,m), 7.2-7.7 (5H,m)

18(9)

NMR(CDCl₃) δ: 1.21 (6H,d,J=7.1 Hz), 1.4-2.6 (6H,m), 2.11 (3H,s), 2.6-3.6 (5H,m), 4.0-5.2 (3H,m), 6.82 (2H,d,J=8.7 Hz), 7.12 (2H,d,J=8.7 Hz)

18(10)

NMR(d₆-DMSO) δ: 1.3-3.8 (18H,m), 4.6-4.9 (1H,m), 5.0-5.3 (1H,m), 6.68 (1H,bs), 7.1-7.6 (5H,m)

18(11)

NMR(CDCl₃) δ: 1.09 (3H,t,J=7.5 Hz), 1.18 (3H,t,J=7.5 Hz), 1.4-3.6 (20H,m), 4.6-4.9 (1H,m), 5.0-5.3 (1H,m), 7.32 (5H,s), 9.46 (1H,bs)

18(12)

NMR(d₆-DMSO+D₂O) δ: 1.19 (3H,t,J=7.1 Hz), 1.3-3.7 (14H,m), 3.82 (3H,s), 4.06 (2H,q,J=7.1 Hz), 4.6-4.8 (1H,m), 5.1-5.3 (1H,m), 7.06 (2H,d,J=8.5 Hz), 7.91 (2H,d, J=8.5 Hz)

18(14)

NMR(CDCl₃) δ: 1.26 (3H,t,J=7.1 Hz), 1.4-2.6 (7H,m), 2.9-3.4 (4H,m), 4.14 (2H,q,J=7.1 Hz), 4.7-4.9 (1H,m), 7.1-7.5 (5H,m), 8.57 (1H,bs)

18(16)

NMR(d₆-DMSO+D₂O) δ: 0.84 (6H,d,J=6.6 Hz), 1.3-2.2 (10H,m), 2.6-3.5 (6H,m), 4.6-4.8 (1H,m), 7.1-7.5 (5H,m)

18(17)

NMR(CDCl₃) δ: 1.4-2.4 (10H,m), 2.6-3.0 (5H,m),3.0-3.8 (1H,m), 4.0-4.5 (1H,m), 4.6-4.8 (1H,m), 6.6-6.9 (2H,m), 7.08 (1H,d, J=7.6 Hz), 7.35 (5H,bs), 8.2-8.8 (1H,m)

18(18)

NMR(CDCl₃) δ: 0.7-1.1 (12H,m), 1.3-3.4 (16H,m), 4.8-5.3 (2H,m), 8.69 (1H,bs)

18(19)

NMR(CDCl₃) δ: 0.88 (6H,d,J=6.1 Hz), 1.0-3.4 (26H,m), 4.9-5.3 (2H,m), 6.8-8.0 (1H,m)

EXAMPLE 19(1)

In a mixture of 0.70 ml of ethanol and 0.30 ml of water were dissolved 0.30 g of 4-(4-isopropylphenoxy)-1-cyclohexanone and 0.21 g of D-penicillamine. The solution thus formed was stirred at ambient temperature for 4 hours. The reaction mixture was poured into a solvent mixture consisting of water and ethyl acetate, and the organic layer was separated. The organic layer was washed successively with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Hexane was added to the residue, and the deposited crystal was collected by filtration. Thus, 0.32 g of (3S)-8-(4-isopropylphenoxy)-2,2-dimethyl-1-thia-4-azaspiro[4.5]decane-3-carboxylic acid was obtained as a colorless crystalline product.

NMR (CDCl₃) δ: 1.1-2.5 (20H,m), 2.7-3.1(1H,m), 3.9-4.5(2H,m), 4.77(2H,bs), 6.7-7.2(4H,m)

19(2)

Using L-penicillamine, the procedure of 19 (1) was repeated to obtain

(3R)-8-(4-isopropylphenoxy)-2,2-dimethyl-1-thia-4-azaspiro[4.5]decane-3-carboxylic acid.

NMR (CDCl₃) δ: 1.2-2.5(20H,m), 2.6-3.1(1H,m), 4.0-4.6(2H,m), 5.83(2H,bs), 6.7-7.4(4H,m)

EXAMPLE 20

The procedure of Example 17 was repeated to obtain the following compounds.

20(1)

(3S)-4-Benzoyl-8-(4-isopropylphenoxy)-2,2-dimethyl-1-thia-4-azaspiro[4.5]decane-3-carboxylic acid

NMR (CDCl₃) δ: 1.22(6H,d,J=6.8 Hz), 1.38(3H,s), 1.69(3H,s), 1.4-3.7(9H,m), 4.0-4.6(2H,m), 6.1-6.6(1H,bs), 6.84(2H,d, J=8.6 Hz), 7.14(2H,d,J=8.6 Hz), 7.0-7.5(5H,m)

20(2)

(3R)-4-Benzoyl-8-(4-isopropylphenoxy)-2,2-dimethyl-1-thia-4-azaspiro[4.5]decane-3-carboxylic acid

NMR (CDCl₃) δ: 1.1-3.8(21H,m), 4.0-4.8(3H,m), 6.8-7.7(9H,m)

EXAMPLE 21

In 56 ml of methylene chloride was dissolved 2.80 g of (3R)-4-benzoyl-8-(4-isopropylphenoxy)-1-thia-4-azaspiro[4.5]decane-3-carboxylic acid, to which were successively added at 0-5° C. 0.56 ml of ethanol, 0.16 g of N,N-dimethylaminopyridine and 1.98 g of dicyclohexyl carbodiimide. After stirring the mixture at ambient temperature for 24 hours, the insoluble matter was filtered off. The filtrate was poured into ice water, pH was adjusted to 2.0 with 2 mol/L hydrochloric acid, and the organic layer was separated. The organic layer thus obtained was washed successively with water, saturated aqueous solution of sodium hydrogen carbonate and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification of the residue by column chromatography [eluent: toluene:ethyl acetate=50:1] gave 0.85 g of ethyl (3R)-4-benzoyl-8-(4-isopropylphenoxy)-1-thia-4-azaspiro[4.5]decane-3-carboxylate as a colorless oily product.

NMR (CDCl₃) δ: 1.21(6H,d,J=6.8 Hz), 1.21(3H,t,J=7.1 Hz), 1.4-2.4(6H,m), 2.6-3.8(5H,m), 4.13(2H,q,J=7.1 Hz), 4.4-4.6(1H,m), 4.7-5.0(1H,m), 6.88(2H,d,J=8.7 Hz), 7.11(2H,d,J=8.7 Hz), 7.35(5H,s)

EXAMPLE 22

The procedure of Example 21 was repeated to obtain the following compounds.

22(1)

Ethyl (3S)-4-benzoyl-8-(4-isopropylphenoxy)-1-thia-4-azaspiro[4.5]decane-3-carboxylate

NMR (CDCl₃) δ:1.21(6H,d,J=6.8 Hz), 1.22(3H,t,J=7.1 Hz), 1.4-2.4(6H,m), 2.6-3.8(5H,m), 4.13(2H,q,J=7.1 Hz), 4.4-4.6(1H,m), 4.8-5.0(1H,m), 6.89(2H,d,J=8.8 Hz), 7.12(2H,d,J=8.8 Hz), 7.3-7.6(5H,m)

22(2)

Ethyl (3R)-4-benzoyl-3-(tert-butoxycarbonyl)-1-thia-4-azaspiro]4.5]decane-8-carboxylate

NMR (CDCl₃) δ: 1.25(3H,t,J=7.1 Hz), 1.39(9H,s), 1.4-2.6(7H,m), 2.9-3.5(4H,m), 4.13(2H,q,J=7.1 Hz), 4.67(1H,dd,J=3.1 Hz,5.0 Hz), 7.34(5H,s)

EXAMPLE 23

In a mixture consisting of 23 ml of ethanol and 23 ml of tetrahydrofuran was dissolved 2.30 g of ethyl (3R)-4-benzoyl-3-(tert-butoxycarbonyl)-1-thia-4-azaspiro[4.5]decane-8-carboxylate. Then, 15.9 ml of 1 mol/L aqueous solution of sodium hydroxide was added at 0-5° C. and the resulting mixture was stirred at ambient temperature for 2 hours. The solvent was distilled off under reduced pressure, the residue thus obtained was added to a mixture of water and ethyl acetate, and the aqueous layer was separated. Ethyl acetate was added to the aqueous layer, pH was adjusted to 2.0 with 2 mol/L hydrochloric acid, and the organic layer was separated. The organic layer was washed successively with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Isopropyl ether was added to the residue and the deposited crystal was collected by filtration. Thus, 1.78 g of (3R)-4-benzoyl-3-(tert-butoxycarbonyl)-1-thia-4-azaspiro[4.5]decane-8-carboxylic acid was obtained as a colorless crystalline product.

NMR (CDCl₃) δ: 1.39(9H,s), 1.4-2.6(7H,m), 2.9-3.5(4H,m), 4.68(1H,dd,J=3.2 Hz,4.6 Hz), 7.35(5H,s), 9.63(1H,bs)

EXAMPLE 24

In 6 ml of methylene chloride was dissolved 0.40 g of (3R)-4-benzoyl-3-(tert-butoxycarbonyl)-1-thia-4-azaspiro[4.5]decane-8-carboxylic acid. After adding 0.17 ml of oxalyl chloride and 0.06 ml of N,N-dimethylformamide at ambient temperature, the resulting mixture was stirred at the same temperature as above for 2 hours. The solvent was distilled off under reduced pressure, and the residue was subjected to an azeotropic distillation treatment with toluene several times. Thus, 0.40 g of a yellow oily product was obtained.

The 0.40 g of the yellow oily product obtained above dissolved in 4 ml of methylene chloride was dropwise added at 0-5° C. to a solution of 0.28 g of 4-isopropylaniline and 0.15 ml of triethylamine in 4 ml of methylene chloride. The resulting mixture was stirred at the same temperature as above for 30 minutes and then at ambient temperature for one hour. The reaction mixture was poured into ice water, pH was adjusted to 2.0 with 2 mol/L hydrochloric acid, and the organic layer was separated. The organic layer thus obtained was washed successively with water, saturated aqueous solution of sodium hydrogen carbonate and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue thus obtained was purified by column chromatography [eluent: hexane:ethyl acetate=3:1] and then treated with a mixture of hexane and isopropyl ether. The deposited crystal was collected by filtration, and there was obtained 0.40 g of tert-butyl (3R)-4-benzoyl-8-[(4-isopropylanilino)carbonyl]-1-thia-4-azaspiro[4.5]-decane-3-carboxylate.

NMR (CDCl₃) δ: 1,21(6H,d,J=6.8 Hz), 1.38(9H,s), 1.5-2.5(7H,m), 2.7-3.5(5H,m), 4.66(1H,dd,J=3.1 Hz,4.8 Hz), 7.0-7.7(10H,m)

EXAMPLE 25

The procedure of Example 24 was repeated to obtain tert-butyl (3R)-4-benzoyl-8-{[(4,5-dimethyl-1,3-thiazol-2-yl)amino]carbonyl}-1-thia-4-azaspiro[4.5]-decane-3-carboxylate.

NMR (CDCl₃) δ: 1.39(9H,s), 1.5-2.5(7H,m), 2.31(6H,s), 2.9-3.5(4H,m), 4.66(1H,dd,J=3.2 Hz,4.6 Hz), 7.34(5H,s), 7.8-8.5(1H,bs)

EXAMPLE 26

In 7 ml of methylene chloride was dissolved 0.35 g of tert-butyl (3R)-4-benzoyl-8-[(4-isopropylanilino)-carbonyl]-1-thia-4-azaspiro[4.5]-decane-3-carboxylate. After adding 1.8 ml of trifluoroacetic acid at 0-5° C., the resulting mixture was stirred at ambient temperature for 6 hours. After distilling off the solvent under reduced pressure, the residue was several times subjected to an azeotropic distillation treatment together with toluene and then purified by column chromatography [eluent: chloroform:ethanol=20:1]. The residue was treated with ethyl ether, and the deposited crystal was collected by filtration to obtain 0.12 g of (3R)-4-benzoyl-8-[(4-isopropylanilino)carbonyl]-1-thia-4-azaspiro[4.5]decane-3-carboxylic acid as a colorless crystalline product.

NMR (d₆-DMSO) δ: 1.17(6H,d,J=6.8 Hz), 1.4-3.7(13H,m), 4.6-4.9(1H,m), 7.0-7.7(9H,m), 9.83(1H,bs)

EXAMPLE 27

The procedure of Example 26 was repeated to obtain (3R)-4-benzoyl-8-{[(4,5-dimethyl-1,3-thiazol-2-yl)amino]-carbonyl}-1-thia-4-azaspiro[4.5]decane-3-carboxylic acid.

NMR (d₆-DMSO) δ: 1.6-2.5(7H,m), 2.15(3H,s), 2.22(3H,s), 2.8-3.8(4H,m), 4.6-4.8(1H,m), 7.38(5H,s), 7.6-8.0(1H,bs), 11.4-12.4(1H,bs)

EXAMPLE 28

In 10 ml of anhydrous tetrahydrofuran was dissolved 0.50 g of (3R)-4-benzoyl-8-(4-isopropylphenoxy)-1-thia-4-azaspiro[4.5]decane-3-carboxylic acid. Then, at 0-5° C., 0.22 g of benzyl 3-aminopropionate, 0.19 g of 1-hydroxybenzotriazole monohydrate and 0.26 g of dicyclohexyl carbodiimide were added successively. After stirring the resulting mixture at the same temperature as above for 30 minutes and then at ambient temperature for 5 hours, the insoluble matter was filtered off. The filtrate was poured into a mixture of water and ethyl acetate, pH was adjusted to 2.0 with 2 mol/L hydrochloric acid, and the organic layer was separated. The organic layer thus obtained was washed successively with water, saturated aqueous solution of sodium hydrogen carbonate and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification of the residue by column chromatography [eluent: hexane:ethyl acetate=2:1] gave 0.55 g of benzyl 3-{[(3R)-4-benzoyl-8-(4-isopropylphenoxy)-1-thia-4-azaspiro[4.5]decan-3-yl]carbonyl}amino-propionate as a colorless oily product.

NMR (CDCl₃) δ: 1.21(6H,d,J=6.8 Hz), 1.4-2.3(6H,m), 2.4-3.8(9H,m), 4.4-4.6(1H,m), 4.7-4.9(1H,m), 5.13(2H,s), 6.87(2H,d,J=8.8 Hz), 6.6-7.0(1H,m), 7.12(2H,d,J=8.8 Hz), 7.33(10H,s)

EXAMPLE 29

In 8 ml of ethanol was dissolved 0.38 g of benzyl 3-({[(3R)-4-benzoyl-8-(4-isopropylphenoxy)-1-thia-4-azaspiro[4.5]decan-3-yl]carbonyl}amino)-propionate. Then, 1.90 ml of 1 mol/L aqueous solution of sodium hydroxide was added at 0-5° C., and the resulting mixture was stirred at ambient temperature for 4 hours. The reaction mixture was poured into a mixture of ice water and ethyl acetate, and the aqueous layer was separated. Ethyl acetate was added to the aqueous layer thus obtained, pH was adjusted to 2.0 with 2 mol/L hydrochloric acid, and the organic layer was separated. The organic layer thus obtained was washed successively with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Thus, 0.30 g of 3-({[(3R)-4-benzoyl-8-(4-isopropylphenoxy)-1-thia-4-azaspiro[4.5]-decan-3-yl]carbonyl}amino)-propionic acid was obtained as a colorless oily product.

NMR (CDCl₃) δ: 1.21 (6H,d,J=6.8 Hz), 1.4-2.3 (6H,m), 2.4-3.8 (9H,m), 4.4-4.6 (1H,m), 4.7-4.9 (1H,m), 6.83 (2H,d,J=8.8 Hz), 7.0-7.5 (6H,m), 7.11 (2H,d,J=8.8 Hz), 8.00 (1H,bs)

EXAMPLE 30

In 4 ml of methanol was suspended 0.40 g of (3R)-4-benzoyl-8-[4-(methoxycarbonyl)phenoxy]-1-thia-4-azaspiro[4.5]decane-3-carboxylic acid. After adding thereto 4.40 ml of 1 mol/L aqueous solution of sodium hydroxide at 0-5° C., the resulting mixture was stirred at ambient temperature for 6 hours. The reaction mixture was poured into ice water, pH was adjusted to 2.0 with 2 mol/L hydrochloric acid, and then the product was extracted with ethyl acetate. The organic layer was washed successively with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Ethyl ether and ethyl acetate was added to the residue, and the deposited crystal was collected by filtration to obtain 0.30 g of (3R)-4-benzoyl-8-(4-carboxyphenoxy)-1-thia-4-azaspiro[4.5]-decane-3-carboxylic acid as a colorless crystalline product.

NMR (d₆-DMSO+D₂O) δ: 1.4-2.4 (6H,m), 3.0-3.7 (4H,m), 4.6-4.9 (2H,m), 7.04 (2H,d,J=8.6 Hz), 7.40 (5H,s),7.92 (2H,d, J=8.6 Hz)

EXAMPLE 31

The procedure of Example 30 was repeated to obtain the following compounds.

31(1)

(3R)-8-(4-Carboxyphenoxy)-4-(3-carboxypropanoyl)-1-thia-4-azaspiro[4.5]decane-3-carboxylic acid

NMR (d₆-DMSO+D₂O) δ: 1.3-3.7 (14H,m) 4.5-4.8 (1H,m), 5.1-5.3 (1H,m), 7.04 (2H,d,J=8.5 Hz), 7.90 (2H,d,J=8.5 Hz)

31(2)

(3R)-4-Benzoyl-8-{[(2-carboxyethyl)amino]-carbonyl}-1-thia-4-azaspiro[4.5]decane-3-carboxylic acid

NMR (d₆-DMSO+D₂O) δ: 1.3-3.6(15H,m), 4.6-4.9(1H,m), 7.1-7.6(5H,bs)

EXAMPLE 32

In 9 ml of anhydrous tetrahydrofuran was dissolved 0.60 g of (3R)-4-benzoyl-8-({[3-(benzoyloxy)-3-oxopropyl]-amino}carbonyl)-1-thia-4-azaspiro[4.5]decane-3-carboxylic acid. At 0-5° C., 0.26 g of L-methionine methyl ester hydrochloride, 0.19 g of 1-hydroxybenzotriazole monohydrate and 0.14 ml of N-methylmorpholine were successively added. After stirring the mixture at the same temperature as above for 30 minutes, 0.27 g of dicyclohexyl carbodiimide was added and the resulting mixture was stirred at the same temperature as above for 30 minutes and then at ambient temperature for 6 hours. The insoluble matter was filtered off, the filtrate was added to a mixture of water and ethyl acetate, pH was adjusted to 2.0 with 2 mol/L hydrochloric acid, and the organic layer was separated. The organic layer was washed successively with water, saturated aqueous solution of sodium hydrogen carbonate and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification of the residue by column chromatography [eluent: toluene:ethyl acetate=1:2] gave 0.62 g of methyl (2S)-2-({[(3R)-4-benzoyl-8-({[3-(benzyloxy)-3-oxopropyl]amino}carbonyl)-1-thia-4-azaspiro[4.5]decan-3-yl]carbonyl}amino)-4-(methylthio)butyrate as a colorless oily product.

NMR (CDCl₃) δ: 1.5-2.8 (13H,m), 2.06 (3H,s), 2.9-3.7 (6H,m), 3.79 (3H,s), 4.5-4.9 (2H,m), 5.15 (2H,s), 6.0-6.3 (1H,m), 6.6-6.9 (1H,m),7.36 (10H,s)

EXAMPLE 33

The procedure of Example 29 was repeated to obtain (2S)-2-{[((3R)-4-benzoyl-8-{[(2-carboxyethyl)amino]-carbonyl}-1-thia-4-azaspiro[4.5]decan-3-yl)carbonyl]amino}-4-(methylthio)butyric acid.

NMR (d₆-DMSO) δ: 1.3-3.8 (19H,m), 2.00 (3H,s), 4.0-4.4 (1H,m), 4.5-4.8 (1H,m), 7.33 (5H,bs), 7.7-8.2 (2H,m), 11.6-13.0 (2H,bs)

EXAMPLE 34

In 5 ml of anhydrous tetrahydrofuran was dissolved 0.50 g of 3-[8-(3-methylbutylidene)-3-oxo-1-thia-4-azaspiro[4.5]decan-4-yl]-propionic acid. After adding 0.25 ml of benzaldehyde and 0.45 g of potassium tert-butoxide at ambient temperature, the resulting mixture was heated under reflux for 6 hours. The reaction mixture was poured into a mixture of water and ethyl acetate, pH was adjusted to 2.0 with 2 mol/L hydrochloric acid, and the organic layer was separated. The organic layer was washed successively with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Isopropyl ether was added to the residue and the deposited crystal was collected by filtration. Thus, 0.32 g of 3-[8-(3-methylbutylidene)-3-oxo-2-(1-phenylmethylidene)-1-thia-4-azaspiro[4.5]decan-4-yl]-propionic acid was obtained as a colorless crystalline product.

NMR (CDCl₃) δ: 0.91 (6H,d,J=6.4 Hz), 1.4-3.0 (13H,m), 3.5-3.9 (2H,m), 5.1-5.3 (1H,m), 7.0-7.8 (7H,m)

EXAMPLE 35

The procedure of Example 10 was repeated to obtain the following compounds.

35(1)

Benzyl 3-[8-(3-methylbutylidene)-3-oxo-2-(1-phenylmethylidene)-1-thia-4-azaspiro[4.5]decan-4-yl-propionate

NMR (CDCl₃) δ: 0.91 (6H,d,J=6.1 Hz), 1.4-3.0 (13H,m), 3.6-4.0 (2H,m), 5.1-5.3 (1H,m), 5.14 (2H,s), 7.2-7.7 (11H,m)

35(2)

tert-Butyl 2-[8-(4-isopropylphenoxy)-3-oxo-4-phenethyl-1-thia-4-azaspiro[4.5]decan-2-yl]-acetate

NMR (CDCl₃) δ: 1.22 (6H,d,J=6.8 Hz), 1.47 (9H,s), 1.5-2.3 (8H,m), 2.4-3.1 (5H,m), 3.2-3.5 (2H,m), 3.9-4.2 (2H,m), 6.81 (2H,d,J=8.6 Hz), 7.13 (2H,d,J=8.6 Hz), 7.27 (5H,s)

EXAMPLE 36

In 7 ml of methylene chloride was dissolved 0.32 g of tert-butyl 2-[8-(4-isopropylphenoxy)-3-oxo-4-phenethyl-1-thia-4-azaspiro[4.5]decan-2-yl]-acetate. After adding 0.33 g of m-chloroperbenzoic acid at 0-5° C., the resulting mixture was stirred at ambient temperature for 24 hours. The reaction mixture was poured into a saturated aqueous solution of sodium hydrogen carbonate, and the organic layer was separated. The organic layer was washed successively with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification of the residue by column chromatography [eluent: hexane:ethyl acetate=8:1] gave 0.17 g of tert-butyl 2-[8-(4-isopropylphenoxy)-1,1,3-trioxo-4-phenethyl-1-thia-4-azaspiro[4.5]decan-2-yl]-acetate as a colorless oily product.

NMR (CDCl₃) δ: 1.24 (6H,d,J=6.8 Hz), 1.50 (9H,s), 1.8-2.5 (8H,m), 2.6-3.9 (7H,m), 4.1-4.3 (1H,m), 4.5-4.7 (1H,m), 6.83 (2H,d,J=8.6 Hz), 7.17 (2H,d,J=8.6 Hz), 7.26 (5H,s)

EXAMPLE 37

The procedure of Example 5 was repeated to obtain 2-[8-(4-isopropylphenoxy)-1,1,3-trioxo-4-phenethyl-1-thia-4-azaspiro[4.5]decan-2-yl]-acetic acid.

NMR (CDCl₃) δ: 1.24 (6H,d,J=6.8 Hz), 1.8-2.5 (8H,m), 2.7-4.0 (7H,m), 4.1-4.4 (1H,m), 4.5-4.7 (1H,m), 6.83 (2H,d,J=8.7 Hz), 6.6-6.8 (1H,bs), 7.17 (2H,d,J=8.7 Hz), 7.27 (5H,s)

EXAMPLE 38

In 4 ml of N,N-dimethylformamide was dissolved 0.29 g of 2-[8-(4-isopropylphenoxy)-3-oxo-4-phenethyl-1-thia-4-azaspiro[4.5]decan-2-yl]-acetic acid. After adding 0.10 g of glycine methyl ester hydrochloride and 0.08 g of N-methylmorpholine at ambient temperature, the resulting mixture was stirred at the same temperature as above for 5 minutes. Then, 0.14 g of 1-hydroxybenzotriazole monohydrate and 0.17 g of dicyclohexyl carbodiimide were added at 0-5° C., and the resulting mixture was stirred at ambient temperature for 24 hours. The reaction mixture was poured into a mixture of water and ethyl acetate, pH was adjusted to 2.0 with 2 mol/L hydrochloric acid, and the organic layer was separated. The organic layer thus obtained was washed successively with water, saturated aqueous solution of sodium hydrogen carbonate and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification of the residue thus obtained by column chromatography [eluent: toluene:ethyl acetate=2:1] gave 0.35 g of methyl 2-({[2-[8-(4-isopropylphenoxy)-3-oxo-4-phenethyl-1-thia-4-azaspiro[4.5]decan-2-yl]acetyl}amino)-acetate as a colorless oily product.

NMR (CDCl₃) δ: 1.23 (6H,d,J=6.8 Hz), 1.4-3.7 (15H,m), 3.77 (3H,s), 4.0-4.3 (3H,m), 4.4-4.6 (1H,m), 6.6-6.9 (1H,bs), 6.82 (2H,d,J=8.9 Hz), 7.16 (2H,d,J=8.9 Hz), 7.29 (5H,s)

EXAMPLE 39

The procedure of Example 8 was repeated to obtain 2-({2-[8-(4-isopropylphenoxy)-3-oxo-4-phenethyl-1-thia-4-azaspiro[4.5]decan-2-yl]acetyl}amino)-acetic acid.

NMR (CDCl₃) δ: 1.23 (6H,d,J=6.8 Hz), 1.4-3.1 (11H,m), 3.1-3.9 (4H,m), 4.0-4.3 (3H,m), 4.4-4.6 (1H,m), 6.82 (2H,d,J=8.5 Hz), 7.15 (2H,d,J=8.5 Hz), 7.2-7.5 (7H,m)

EXAMPLE 40

In 15 ml of methylene chloride was suspended 0.30 g of 1H-2-pyrrolecarboxylic acid. To the suspension thus obtained were added at 0-5° C. 0.28 ml of oxalyl chloride and 0.06 ml of N,N-dimethylformamide, and the resulting mixture was stirred at ambient temperature for 24 hours. The solvent was distilled off under reduced pressure from the reaction mixture, and the residue was subjected to an azeotropic distillation treatment with toluene. Thus, 0.36 g of 1H-2-pyrrolecarbonyl chloride was obtained as a brown crystalline product.

In 6 ml of methylene chloride were dissolved 0.30 g of (3R)-8-(4-isopropylphenoxy)-1-thia-4-azaspiro[4.5]decane-3-carboxylic acid and 0.47 ml of triethylamine. After adding 0.18 g of 1H-2-pyrrolecarbonyl chloride at 0-5° C., the resulting mixture was stirred at ambient temperature for 24 hours. The reaction mixture was poured into ice water, pH was adjusted to 2.0 with 2 mol/L hydrochloric acid, and the organic layer was separated. The organic layer thus obtained was washed successively with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. After purifying the residue by column chromatography [eluent: chloroform:ethanol=200:1], isopropyl ether was added and the deposited crystal was collected by filtration. Thus, 0.14 g of (3R)-8-(4-isopropylphenoxy)-4-(1H-2-pyrrolylcarbonyl)-1-thia-4-azaspiro[4.5]decane-3-carboxylic acid was obtained as a yellow crystalline product.

NMR (d₆-DMSO) δ: 1.17 (6H,d,J=6.8 Hz), 1.5-2.4 (6H,m), 2.4-3.8 (6H,m), 4.5-4.7 (1H,m), 5.3-5.6 (1H,m), 6.0-6.4 (2H,m), 6.8-7.4 (6H,m)

EXAMPLE 41

The procedure of Example 40 was repeated to obtain the following compounds.

41(1)

(3R)-8-(4-Isopropylphenoxy)-4-(2-thienylcarbonyl)-1-thia-4-azaspiro[4.5]decane-3-carboxylic acid

NMR (CDCl₃) δ: 1.21 (6H,d,J=6.8 Hz), 1.4-2.4 (6H,m), 2.6-3.8 (5H,m), 4.4-4.6 (1H,m), 5.1-5.3 (1H,m), 6.8-7.5 (8H,m)

41(2)

(3R)-8-(4-Isopropylphenoxy)-4-(3-quinolylcarbonyl)-1-thia-4-azaspiro[4.5]decane-3-carboxylic acid

NMR (CDCl₃) δ: 1.22 (6H,d,J=6.8 Hz), 1.4-2.5 (6H,m), 2.7-4.0 (5H,m), 4.5-4.8 (2H,m), 6.8-7.3 (5H,m), 7.5-8.3 (5H,m), 9.2-9.4 (1H,m)

41(3)

(3R)-8-(4-Isopropylphenoxy)-4-[(2-methyl-1,3-thiazol-4-yl)carbonyl]-1-thia-4-azaspiro[4.5]decane-3-carboxylic acid

NMR (CDCl₃) δ: 1.22 (6H,d,J=6.8 Hz), 1.4-2.3 (6H,m), 2.55 (3H,s), 2.6-3.9 (5H,m), 4.4-4.6 (1H,m), 5.9-6.0 (1H,m), 6.93 (2H,d,J=8.8 Hz), 7.12 (2H,d,J=8.8 Hz), 7.97 (1H,s), 8.9-9.2 (1H,bs)

41(4)

(3R)-8-(4-Isopropylphenoxy)-4-(2-pyrazinylcarbonyl)-1-thia-4-azaspiro[4.5]decane-3-carboxylic acid

NMR (d₆-DMSO) δ: 1.17 (6H,d,J=6.8 Hz), 1.3-2.3 (6H,m), 2.4-3.8 (5H,m), 4.5-4.7 (1H,m), 5.4-5.6 (1H,m), 6.8-7.3 (5H,m), 8.5-9.0 (3H,m)

41(5)

(3R)-8-(4-Isopropylphenoxy)-4-(4-methoxybenzoyl)-1-thia-4-azaspiro[4.5]decane-3-carboxylic acid

NMR (CDCl₃) δ: 1.21 (6H,d,J=6.8 Hz), 1.4-2.4 (6H,m), 2.7-3.6 (5H,m), 3.79 (3H,s), 4.4-4.5 (1H,m), 4.8-5.0 (1H,m), 6.7-7.4 (8H,m), 9.4-9.6 (1H,bs)

41(6)

(3R)-4-{4-[(Diethylamino)carbonyl]benzoyl}-8-(4-isopropylphenoxy)-1-thia-4-azaspiro[4.5]decane-3-carboxylic acid

NMR (CDCl₃) δ: 1.0-1.3 (12H,m), 1.3-2.4 (6H,m) 2.7-3.8 (9H,m), 4.4-4.7 (2H,m), 6.91 (2H,d,J=8.5 Hz), 7.12 (2H,d,J=8.5 Hz), 7.36 (4H,s), 8.4-8.6 (1H,bs)

Further, in the same manner as above, the compounds of Tables 64 and 65 were obtained.

TABLE 64

No. A R^(2b) R³ 41 (7)

41 (8)

41 (9)

41 (10)

41 (11)

TABLE 65 No. A R^(2b) R³ 41 (12)

41 (13)

41 (14)

41 (15)

Properties of the compounds shown in Tables 64 and 65 are as follows.

41(7)

NMR(CDCl₃) δ: 0.7-1.1 (12H,m), 1.2-3.4 (18H,m), 4.8-5.3 (2H,m), 6.9-7.4 (1H,m)

41(8)

NMR(CDCl₃) δ: 0.8-1.1 (12H,m), 1.3-3.5 (18H,m), 4.9-5.3 (2H,m), 8.0-8.2 (1H,m)

41(9)

NMR(CDCl₃) δ: 0.7-1.1 (9H,m), 1.1-3.6 (19H,m), 4.8-5.3 (2H,m), 8.37 (1H,bs)

41(10)

NMR(CDCl₃) δ: 0.87(12H,d,J=6.1 Hz), 0.1-3.4 (20H,m), 4.8-5.3 (2H,m), 6.05 (1H,bs)

41(11)

NMR(CDCl₃) δ: 0.7-1.1 (9H,m), 1.1-3.5 (19H,m), 4.8-5.3 (2H,m), 6.88 (1H,bs)

41(12)

NMR(CDCl₃) δ: 0.6-3.7 (28H,m), 4.8-5.1 (2H,m)

41(13)

NMR(CDCl₃) δ: 0.3-3.6 (32H,m), 4.8-5.5 (2H,m), 8.00 (1H,bs)

41(14)

NMR(CDCl₃) δ: 1.0-2.4 (23H,m), 2.6-3.7 (8H,m), 4.0-4.6 (1H,m), 4.9-5.2 (1H,m), 6.7-7.5 (9H,m)

41(15)

NMR(CDCl₃) δ: 1.1-4.8 (22H,m), 5.0-5.2 (1H,m), 6.0-6.3 (1H,m), 6.4-7.5 (6H,m), 10.0-10.8 (2H,m)

EXAMPLE 42

In 80 ml of acetone was dissolved 8.50 g of 2-[4-[3-(benzyloxy)-3-oxopropyl]-8-(3-methylbutylidene)-3-oxo-1-thia-4-azapiro[4.5]decan-2-yl]-acetic acid. After adding thereto 40 ml of an aqueous solution containing 1.50 g of sodium hydrogen carbonate, the resulting mixture was stirred at ambient temperature for 30 minutes. The solvent was distilled off under reduced pressure and the residue was subjected to an azeotropic distillation treatment with ethanol to obtain 8.00 g of sodium 2-[4-[3-(benzyloxy)-3-oxopropyl]-8-(3-methylbutylidene)-3-oxo-1-thia-4-azaspiro[4.5]decan-2-yl]-acetate.

NMR(d₆-DMSO) δ: 0.86 (6H,d,J=6.4 Hz), 1.4-2.9 (13H,m), 3.2-3.7 (4H,m), 3.9-4.1 (1H,m), 5.09 (2H,s), 5.0-5.3 (1H,m), 7.37 (5H,s)

EXAMPLE 43

The procedure of 19(2) was repeated to obtain (3R)-2,2-dimethyl-8-(3-methylbutylidene)-1-thia-4-azaspiro[4.5]decane-3-carboxylic acid

NMR (CDCl₃) δ: 1.1-2.8(17H,m), 4.03(1H,s), 5.0-5.3(1H,m)

EXAMPLE 44

The procedure of Example 40 was repeated to obtain (3R)-2,2-dimethyl-8-(3-methylbutylidene)-4-(4-methylpentanoyl)-1-thia-4-azaspiro[4.5]decane-3-carboxylic acid

NMR (CDCl₃) δ: 0.5-3.5(34H,m), 4.52(1H,s), 5.0-5.3(1H,m), 8.96(1H,bs)

EXAMPLE 45

The procedure of Example 1 was repeated to obtain 2-[4-[2-(tert-butoxy)-2-oxoethyl]-8-(3-methylbutylidene)-3-oxo-1-thia-4-azaspiro[4.5]decan-2-yl]-acetic acid.

NMR (CDCl₃) δ: 0.88 (6H,d,J=6.4 Hz), 1.2-2.9 (21H,m), 3.32 (1H,dd,J=17.1,4.9 Hz), 3.89 (2H,d,J=2.2 Hz), 4.24 (1H,dd,J=4.7,5.4 Hz), 5.0-5.4 (1H,m)

EXAMPLE 46

In 10 ml of N,N-dimethylformamide was dissolved 1.0 g of 2-[4-[2-(tert-butoxy)-2-oxoethyl]-8-(3-methylbutylidene)-3-oxo-1-thia-4-azaspiro[4.5]decan-2-yl]-acetic acid. After adding 0.42 ml of 2-iodopropane and 0.67 g of anhydrous potassium carbonate at ambient temperature, the resulting mixture was stirred at ambient temperature for 17 hours. The reaction mixture was poured into a mixture of ice water and ethyl acetate, pH was adjusted to 2.0 with 2 mol/L hydrochloric acid, and the organic layer was separated. The organic layer thus obtained was washed successively with water, saturated aqueous solution of sodium hydrogen carbonate and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification of the residue by column chromatography [eluent: hexane:ethyl acetate=17:3] gave 1.0 g of isopropyl 2-[4-[2-(tert-butoxy)-2-oxoethyl]-8-(3-methylbutylidene)-3-oxo-1-thia-4-azaspiro[4.5]decan-2-yl]-acetate as a light yellow oily product.

NMR (CDCl₃) δ: 0.88 (6H,d,J=6.4 Hz), 1.1-2.8 (26H,m), 3.26 (1H,dd,J=16.8,3.7 Hz), 3.8-4.3 (4H,m), 4.8-5.3 (2H,m)

EXAMPLE 47

In 3 ml of diethyl ether was dissolved 0.33 g of isopropyl 2-[4-[2-(tert-butoxy)-2-oxoethyl]-8-(3-methylbutylidene)-3-oxo-1-thia-4-azaspiro[4.5]decan-2-yl]-acetate. Then, 1 ml of a 5.39 mol/L solution of dry hydrogen chloride in dioxane was added and the resulting mixture was stirred at the same temperature as above for 2 hours. Further, 1 ml of 5.39 mol/L solution of dry hydrogen chloride in dioxane was added and the resulting mixture was stirred for one hour, after which 3 ml of 5.39 mol/L solution of dry hydrogen chloride in dioxane was added and the resulting mixture was stirred for one hour. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography [eluent: chloroform]. Then, hexane was added, and the deposited crystal was collected by filtration. Thus, 0.08 g of 2-[2-(2-isopropoxy-2-oxoethyl)-8-(3-methylbutylidene)-3-oxo-1-thia-4-azaspiro[4.5]decan-4-yl]-acetic acid was obtained as a colorless crystalline product.

NMR (CDCl₃) δ: 0.87 (6H,d,J=6.3 Hz), 1.26 (6H,d,J=6.1 Hz), 1.3-2.8 (11H,m), 3.21 (1H,dd,J=16.6,3.8 Hz), 3.9-4.4 (4H,m), 4.9-5.3 (2H,m), 7.10 (1H,bs)

EXAMPLE B-1

In 5 ml of methylene chloride was suspended 0.25 g of 4-isopropylbenzoic acid. Then, at ambient temperature, 0.12 ml of thionyl chloride and 0.03 ml of N,N-dimethylformamide were added. After stirring the mixture at the same temperature as above for one hour, the solvent was distilled off under reduced pressure, and an azeotropic distillation treatment using toluene was carried out to obtain 0.25 g of 4-isopropylbenzoic acid chloride. To a suspension of 0.50 g of trifluoroacetic acid salt of 2-(4-benzyl-3-oxo-1-thia-4,8-diazaspiro[4.5]decan-2-yl]-acetic acid in 5 ml methylene chloride were successively added dropwise at 0-5° C. 0.64 ml of triethylamine and a solution of 0.25 g of 4-isopropylbenzoic acid chloride in 5 ml methylene chloride. The resulting mixture was stirred at ambient temperature for 24 hours. The reaction mixture was poured into ice water, pH was adjusted to 1.0 with 2 mol/L hydrochloric acid, and the organic layer was separated. The organic layer was washed successively with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification of the residue by column chromatography [eluents: toluene:ethyl acetate=1:1, followed by chloroform] gave 0.30 g of 2-[4-benzyl-8-(4-isopropylbenzoyl)-3-oxo-1-thia-4,8-diazaspiro[4.5]-decan-2-yl]-acetic acid as a light yellow solid product.

NMR (CDCl₃) δ: 1.24 (6H,d,J=6.8 Hz), 1.4-2.4 (4H,m), 2.5-3.6 (5H,m), 3.6-4.8 (5H,m), 7.26 (9H,bs), 8.3-8.5 (1H,bs)

EXAMPLE B-2

The procedure of Example B-1 was repeated to obtain the following compounds.

B-2(1)

2-{4-Benzyl-8-[4-(methoxycarbonyl)benzoyl]-3-oxo-1-thia-4,8-diazaspiro[4.5]decan-2-yl]-acetic acid

NMR (CDCl₃) δ: 1.4-2.3 (4H,m), 2.5-3.8 (5H,m), 3.93 (3H,s), 4.2-4.9 (4H,m), 7.27 (5H,s), 7.40 (2H,d,J=8.1 Hz), 8.07 (2H,d,J=8.1 Hz), 7.8-8.0 (1H,bs)

B-2(2)

2-{4-Benzyl-8-[(4-methylphenyl)sulfonyl]-3-oxo-1-thia-4,8-diazaspiro[4.5]decan-2-yl]-acetic acid

NMR (CDCl₃) δ: 1.5-1.8 (2H,m), 2.0-2.9 (5H,m), 2.44 (3H,s), 3.1-3.5 (1H,m), 3.7-4.0 (2H,m), 4.1-4.3 (1H,m), 4.46 (1H,d,J=14.0 Hz), 4.68 (1H,d,J=14.0 Hz), 7.1-7.5 (7H,m), 7.61 (2H,d,J=8.1 Hz), 7.9-8.3 (1H,bs)

EXAMPLE B-3

In 2.5 ml of ethanol was dissolved 0.51 g of ethyl 4-[2-(2-ethoxy-2-oxoethyl)-3-oxo-4-phenethyl-1-thia-4,8-diazaspiro[4.5]decan-8-yl]-oxobutanoate. After adding 2.5 ml of 1 mol/L aqueous solution of sodium hydroxide at 0-5° C., the resulting mixture was stirred at ambient temperature for 1.5 hours. The reaction mixture was poured into a mixture of ice water and ethyl acetate, pH was adjusted to 2.0 with 2 mol/L hydrochloric acid, and the organic layer was separated. The organic layer thus obtained was washed successively with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Thus, 0.34 g of 4-[2-(carboxymethyl)-3-oxo-4-phenethyl-1-thia-4,8-diazaspiro[4.5]decan-8-yl]-4-oxobutanoic acid was obtained as a yellow oily product.

NMR (d₆-DMSO) δ: 1.4-4.7(19H,m), 7.2-7.8(7H,m)

EXAMPLE B-4

The procedure of Example B-3 was repeated to obtain the compounds shown in Table 66.

TABLE 66

No. R^(1h) R₂ 4 (1)

4 (2)

4(3)

4 (4)

4 (5)

4 (6)

4 (7)

4 (8)

4 (9)

Properties of the compounds of Table 66 are as follows.

B-4(1)

NMR (CDCl₃) δ: 1.3-2.2 (4H,m), 2.6-3.6 (6H,m), 3.76 (2H,s), 3.8-4.8 (5H,m), 7.0-7.8 (11H,m)

B-4(2)

NMR (CDCl₃) δ: 1.4-2.2 (6H,m), 2.2-4.0 (13H,m), 4.1-4.3 (1H,m),4.6-4.9 (1H,m), 7.0-7.7 (11H,m)

B-4(3)

NMR (CDCl₃) δ: 1.6-2.2 (4H,m), 2.4-3.8 (8H,m), 4.0-4.4 (2H,m), 4.6-5.0 (1H,m), 6.3-6.7 (1H,m), 6.85 (1H,d,J=15.4 Hz), 7.1-7.6 (10H,m), 7.70 (1H,d,J=15.4 Hz)

B-4(4)

NMR(d₆-DMSO) δ: 0.8-1.1 (6H,m), 1.4-2.2 (7H,m), 2.3-4.7 (12H,m), 7.28 (5H,s), 8.1-8.6 (3H,bs)

B-4(5) (Measured in the form of sodium salt)

NMR(d₆-DMSO) δ: 0.94 (6H,d,J=5.9 Hz), 1.0-3.6 (17H,m), 1.83 (3H,s), 3.8-4.8 (4H,m), 6.7 (1H,bs), 8.0-8.4 (2H,m)

B-4(6)

NMR(CDCl₃) δ: 0.93 (6H,d,J=5.4 Hz), 1.1-2.5 (7H,m),2.5-3.6 (10H,m), 3.9-4.9 (3H,m), 8.9 (2H,bs)

B-4(7)

NMR(d₆-DMSO) δ: 1.2-2.0 (4H,m), 2.4-3.8 (8H,m), 3.8-4.2 (2H,m), 4.3-4.7 (1H,m), 5.4-5.8 (2H,m), 7.1-7.5 (11H,m)

B-4(8)

NMR(CDCl₃) δ: 1.1-2.4 (4H,m), 2.4-3.8 (5H,m), 3.9-4.9 (4H,m), 7.28 (5H,s), 7.39 (2H,d,J=8.0 Hz), 8.07 (2H,d,J=8.0 Hz), 8.6-9.0 (2H,bs)

B-4(9)

NMR(d₆-DMSO+D₂O) δ: 1.2-3.7 (12H,m), 1.41 (9H,s), 3.6-4.3 (3H,m), 12.4 (2H,bs)

EXAMPLE B-5

In 1.4 ml of ethanol was dissolved 0.31 g of 4-[2-(carboxymethyl)-3-oxo-4-phenethyl-1-thia-4,8-diazaspiro[4.5]decan-8-yl]-4-oxobutanoic acid. After adding 1.36 ml of 1 mol/L aqueous solution of sodium hydroxide at 0-5° C., the resulting mixture was stirred at ambient temperature for 5 hours. The reaction mixture was poured into a mixture of ice water and ethyl acetate, and the aqueous layer was separated. The aqueous layer thus obtained was concentrated under reduce pressure to obtain 0.32 g of disodium 4-[2-(carboxymethyl)-3-oxo-4-phenethyl-1-thia-4,8-diazaspiro[4.5]decan-8-yl]-4-oxobutanoate as a colorless solid product.

EXAMPLE C-1

DMF was added to 1.875 g (1.200 mmol) of Rink Amide MBHA resin to swell the resin. Then, 2 ml of 20% piperidine/DMF solution was added and shaken for 20 minutes. The resin was six times washed with DMF, 1.28 g of Fmoc-Leu-OH, 552 mg of HOBt.H₂O, 0.58 ml of DIPCDI and 18 ml of DMF were added and shaken for 90 minutes. After filtering off the liquid phase, the resin was six times washed with DMF. Then, 24 ml of 20% piperidine/DMF solution was added and shaken for 20 minutes. The resin was six times washed with DMF, and then 1.903 g of (3R)-4-benzoyl-8-[(9H-fluoren-9-ylmethoxy)carbonyl]-1-thia-4,8-diazaspiro[4.5]decan-3-carboxylic acid, 552 mg of HOBt.H₂O, 0.58 ml of DIPCDI and 18 ml of DMF were added and shaken for 90 minutes. After filtering off the liquid phase, the resin was six times washed with DMF. The resin was divided into 15 equal portions, and 2 ml of 20% piperidine/DMF solution was added to one of the portions and shaken for 20 minutes. The resin was six times washed with DMF, and 113 mg of Fmoc-Leu-OH, 37 mg of HOBt.H₂O, 39 μL of DIPCDI and 1.2 ml of DMF were added and shaken for 2 hours. After filtering off the liquid phase, the resin was washed with DMF six times. Then, 2 ml of 20% piperidine/DMF solution was added and shaken for 20 minutes. After filtering off the liquid phase, the resin was six times washed with DMF. Then, 1.2 ml of DMF-DCM (1:1) mixture, 0.29 ml of acetic anhydride and 0.53 ml of DIEA were added and shaken for one hour. After filtering off the liquid phase, the resin was washed four times with DMF and three times with DCM. The resin thus obtained was shaken for four hours together with 6 ml of TFA-methylene chloride (1:1). The insoluble matter was filtered off, the filtrate was concentrated under reduced pressure, 20 ml of diethyl ether was added to the residue, and the resulting crystal was collected by filtration to obtain 46 mg of (3R)-8-[(2S)-2-(acetylamino)-4-methylpentanoyl]-N -[(1S)-1-(aminocarbonyl)-3-methylbutyl]-4-benzoyl-1-thia-4,8-diazaspiro[4.5]decane-3-carboxamide.

EXAMPLE C-2

The procedure of Example C-1 was repeated to obtain the following compounds.

TABLE 67

R^(1h) R^(18a) R² calcd. found Ac-Leu NH₂ COC₆H₅ 460.6 461.4 M + H Ac-Asp NH₂ COC₆H₅ Ac-Asn NH₂ COC₆H₅ Ac-Glu NH₂ COC₆H₅ Ac-Gln NH₂ COC₆H₅ Ac-Phe NH₂ COC₆H₅ Ac-Lys NH₂ COC₆H₅ Ac-Arg NH₂ COC₆H₅ Ac-His NH₂ COC₆H₅ Ac-Tyr NH₂ COC₆H₅ nC₃H₇CO NH₂ COC₆H₅ 4-ClC₆H₄CHCHCO NH₂ COC₆H₅ 503.62 504.4 M + H 4-ClC₆H₄CH₂CO NH₂ COC₆H₅ 3-PyCO NH₂ COC₆H₅ 4-PyCO NH₂ COC₆H₅ Ac-Leu Leu-NH₂ COC₆H₅ 573.76 574.4 M + H Ac-Asp Leu-NH₂ COC₆H₅ Ac-Asn Leu-NH₂ COC₆H₅ Ac-Glu Leu-NH₂ COC₆H₅ Ac-Gln Leu-NH₂ COC₆H₅ Ac-Phe Leu-NH₂ COC₆H₅ Ac-Lys Leu-NH₂ COC₆H₅ Ac-Arg Leu-NH₂ COC₆H₅ Ac-His Leu-NH₂ COC₆H₅ Ac-Tyr Leu-NH₂ COC₆H₅ nC₃H₇CO Leu-NH₂ COC₆H₅ 4-ClC₆H₄CHCHCO Leu-NH₂ COC₆H₅ 4-ClC₆H₄CH₂CO Leu-NH₂ COC₆H₅

EXAMPLE C-3

DMF was added to 173 mg (0.100 mmol) of Wang resin to swell the resin. Then, 90 mg of Fmoc-Gly-OH, 1.22 mg of DMAP, 48 μL of DIPCDI and 1.2 ml of DMF were added to the resin and shaken for 2 hours. After filtering off the liquid phase, the resin was six times washed with DMF. Then, 2 ml of 20% piperidine/DMF solution was added and shaken for 20 minutes. After washing the resin six times with DMF, 160 mg of (3R)-4-benzoyl-8-[(9H-fluoren-9-ylmethoxy)carbonyl]-1-thia-4,8-diazaspiro[4.5]decane-3-carboxylic acid, 46 mg of HOBt.H₂O, 48 μL of DIPCDI and 1.2 ml of DMF were added and shaken for 90 minutes. After filtering off the liquid phase, the resin was six times washed with DMF. Then, 2 ml of 20% piperidine/DMF solution was added and shaken for 20 minutes. The resin was six times washed with DMF, and then 266 mg of Fmoc-Arg(Pmc)-OH, 62 mg of HOBt.H₂O, 64 μL of DIPCDI and 1.2 ml of DMF were added and shaken for 2 hours. After filtering off the liquid phase, the resin was washed with DMF six times. Then, 2 ml of 20% piperidine/DMF solution was added and shaken for 20 minutes. After filtering off the liquid phase, the resin was washed with DMF six times. Then, 1.2 ml of DMF-DCM (1:1) mixture, 0.29 ml of acetic anhydride and 0.53 ml of DIEA were added and shaken for one hour. The liquid phase was filtered off, and the resin was washed four times with DMF and three times with DCM. Then, 6 ml of TFA-methylene chloride (1:1) was added and shaken for 4 hours. The insoluble matter was filtered off, the filtrate was concentrated under reduced pressure, 20 ml of diethyl ether was added to the residue, and the resulting crystal was collected by filtration to obtain 66 mg of trifluoroacetic acid salt of 2-({[(3R)-8-((2S)-2-(acetylamino)-5-{[amino(imino)methyl]amino}pentanoyl)-4-benzoyl-1-thia-4,8-diazaspiro[4.5]decan-3-yl]-carbonyl}amino)-acetic acid.

EXAMPLE C-4

The procedure of Example C-3 was repeated to obtain the following compounds.

TABLE 68

R^(1h) R^(18a) R² calcd. found Ac-Leu Leu-OH COC₆H₅ 574.75 575.4 M + H Ac-Asp Leu-OH COC₆H₅ Ac-Asn Leu-OH COC₆H₅ Ac-Gln Leu-OH COC₆H₅ Ac-Gln Leu-OH COC₆H₅ Ac-Phe Leu-OH COC₆H₅ Ac-Lys Leu-OH COC₆H₅ 589.76 590.4 M + H Ac-Arg Leu-OH COC₆H₅ 617.77 618.4 M + H Ac-His Leu-OH COC₆H₅ Ac-Tyr Leu-OH COC₆H₅ 4-ClC₆H₄CHCHCO Leu-OH COC₆H₅ 584.3 584.4 M + H 4-ClC₆H₄CH₂CO Leu-OH COC₆H₅ Ac-Arg Ala-OH COC₆H₅ Ac-Arg Asp-OH COC₆H₅ Ac-Arg Glu-OH COC₆H₅ Ac-Arg Phe-OH COC₆H₅ Ac-Arg Lys-CH COC₆H₅ Ac-Arg Tyr-OH COC₆H₅ Ac-Arg Pro-OH COC₆H₅ Ac-Arg β-Ala-OH COC₆H₅ Ac-Arg D-ala-OH COC₆H₅ Ac-Arg Leu-OH COCH₃ H-Arg Leu-OH COCH₃ 4-ClC₆H₄CHCHCO Leu-OH COCH₃ 4-ClC₆H₄CH₂CO Leu-OH COCH₃ 4-H₂N(HN)CC₆H₄CO Leu-OH COCH₃ 3-(2-Thienyl)-2-propenoyl Leu-OH COCH₃ 3-(3-Pyridyl)-2-propenoyl Leu-OH COCH₃ H-Arg Leu-OH COC₆H₅ 4-H₂N(HN)CC₆H₄CO Leu-OH COC₆H₅ 3-(2-Thienyl)-2-propenoyl Leu-OH COC₆H₅ 3-(3-Pyridyl)-2-propenoyl Leu-OH COC₆H₅ 2-Oxo-2H-pyran-5-carbonyl Leu-OH COC₆H₅ 3-Pyridylcarbonyl Leu-OH COC₆H₅ Ac-Arg Gly-OH COCH₃ Ac-Arg Gly-Gly-OH COCH₃ Ac-Arg D-ala-OH COCH₃ Ac-Arg β-Ala-OH COCH₃ H-Cit Leu-OH COCH₃ Ac-Cit Leu-OH COCH₃

EXAMPLE C-5

DMF was added to 182 mg (0.100 mmol) of Rink amide MBHA resin to swell the resin. Then, 2 ml of 20% piperidine/DMF solution was added and shaken for 20 minutes. After washing the resin six times with DMF, 106 mg of Fmoc-Leu-OH, 46 mg of HOBt.H₂O, 47 μL of DIPCDI and 2 ml of DMF were added and shaken for 90 minutes. After filtering off the liquid phase, the resin was six times washed with DMF. Then, 2 ml of 20% piperidine/DMF solution was added and shaken for 20 minutes. After washing the resin with DMF six times, 190 mg of 2-{4-[3-(benzoyloxy)-3-oxopropyl]-8-[(9H-fluoren-9-ylmethoxy) carbonyl]-3-oxo-1-thia-4,8-diazaspiro[4.5]decan-2-yl}-acetic acid, 46 mg of HOBt.H₂O, 47 μL of DIPCDI and 2 ml of DMF were added and shaken for 90 minutes. After filtering off the liquid phase, the resin was washed six times with DMF. Then, 2 ml of 20% piperidine/DMF solution was added and shaken for 20 minutes. After washing the resin six times with DMF, 115 mg of Fmoc-Ser(tBu)-OH, 46 mg of HOBt.H₂O, 47 μL of DIPCDI and 2 ml of DMF were added and shaken for 90 minutes. After filtering off the liquid phase, the resin was washed six times with DMF. Then, 2 ml of 20% piperidine/DMF solution was added and shaken for 20 minutes. After filtering off the liquid phase, the resin was washed six times with DMF. Then, 2 ml of DMF-DCM (1:1) mixture, 0.29 ml of acetic anhydride and 0.53 ml of DIEA were added, and shaken for 40 minutes. After filtering off the liquid phase, the resin was washed four times with DMF and three times with DCM. Then, 6 ml of TFA-methylene chloride (1:1) was added and shaken for 4 hours. The insoluble matter was filtered off, the filtrate was concentrated under reduced pressure, 20 ml of diethyl ether was added to the residue, and the resulting crystal was collected by filtration to obtain 45 mg of benzyl 3-[8-[(2S)-2-(acetylamino)-3-hydroxypropanoyl]-2-(2-{[(1S)-1-(aminocarbonyl)-3-methylbutyl]amino}-2-oxoethyl)-3-oxo-1-thia-4,8-diazaspiro[4,5]decan-4-yl]-propionate.

EXAMPLE C-6

The procedure of Example C-5 was repeated to obtain the following compounds.

TABLE 69

R^(1h) R¹³ R² k calcd. found Ac—Asn Leu—NH₂ CH₂CH₂CO₂CH₂C₆H₅ 1 660.79 661.4 M + H Ac—Ala Leu—NH₂ CH₂CH₂CO₂CH₂C₆H₅ 1 617.77 618.3 M + H Ac—Asp Leu—NH₂ CH₂CH₂CO₂CH₂C₆H₅ 1 661.78 662.3 M + H Ac—Leu Asp—NH₂ CH₂CH₂CO₂CH₂C₆H₅ 1 661.78 662.3 M + H Ac—Asp Asp—NH₂ CH₂CH₂CO₂CH₂C₆H₅ 1 663.72 662.4 M + H Ac—Gln Asp—NH₂ CH₂CH₂CO₂CH₂C₆H₅ 1 676.75 677.3 M + H Ac—Ser Asp—NH₂ CH₂CH₂CO₂CH₂C₆H₅ 1 635.71 636.3 M + H Ac—Asn Asp—NH₂ CH₂CH₂CO₂CH₂C₆H₅ 1 662.72 663.3 M + H Ac—Ala Asp—NH₂ CH₂CH₂CO₂CH₂C₆H₅ 1 619.71 620.2 M + H Ac—Leu Gln—NH₂ CH₂CH₂CO₂CH₂C₆H₅ 1 674.82 675.4 M + H Ac—Gln Gln—NH₂ CH₂CH₂CO₂CH₂C₆H₅ 1 689.79 690.3 M + H Ac—Ser Gln—NH₂ CH₂CH₂CO₂CH₂C₆H₅ 1 648.74 649.3 M + H Ac—Asn Gln—NH₂ CH₂CH₂CO₂CH₂C₆H₅ 1 675.77 676.3 M + H Ac—Ala Gln—NH₂ CH₂CH₂CO₂CH₂C₆H₅ 1 632.74 633.3 M + H Ac—Leu Leu—NH₂ CH₂CH₂CO₂CH₂C₆H₅ 1 659.85 660.4 M + H Ac—Gln Leu—NH₂ CH₂CH₂CO₂CH₂C₆H₅ 1 674.82 675.4 M + H Ac—Glu Asp—NH₂ CH₂CH₂CO₂CH₂C₆H₅ 1 677.74 678.4 M + H Ac—Asp Asn—NH₂ CH₂CH₂CO₂CH₂C₆H₅ 1 662.72 661.4 M − H Ac—Asn Asn—NH₂ CH₂CH₂CO₂CH₂C₆H₅ 1 661.74 660.4 M − H Ac—Asp Glu—NH₂ CH₂CH₂CO₂CH₂C₆H₅ 1 677.74 676.4 M − H Ac—Asn Glu—NH₂ CH₂CH₂CO₂CH₂C₆H₅ 1 676.75 675.4 M − H Ac—Glu Glu—NH₂ CH₂CH₂CO₂CH₂C₆H₅ 1 691.77 690.4 M − H Ac—Gln Glu—NH₂ CH₂CH₂CO₂CH₂C₆H₅ 1 690.78 689.4 M − H Ac—Asp Gln—NH₂ CH₂CH₂CO₂CH₂C₆H₅ 1 676.75 675.4 M − H Ac—Glu Gln—NH₂ CH₂CH₂CO₂CH₂C₆H₅ 1 690.78 689.4 M − H Ac—D-Ala D-Ala—NH₂ CH₂CH₂CO₂CH₂C₆H₅ 1 575.7 598.4 M + Na Ac—Asn D-Ala—NH₂ CH₂CH₂CO₂CH₂C₆H₅ 1 618.71 641.4 M + Na Ac—D-Ala Asn—NH₂ CH₂CH₂CO₂CH₂C₆H₅ 1 618.71 641.4 M + Na

EXAMPLE C-7

Using Wang resin, Fmoc-Leu-OH, Fmoc-Arg(Pmc)-OH and 2-{4-benzyl-8-[(9H-fluoren-9-ylmethoxy)carbonyl]-3-oxo-1-thia-4,8-diazaspiro[4.5]decan-2-yl}-acetic acid, the procedure of Example C-3 was repeated to obtain (2S)-2-({2-[8-((2S)-2-(acetylamino)-5-{[amino(imino)methyl]amino}-pentanoyl)-4-benzyl-3-oxo-1-thia-4,8-diazaspiro[4.5]decan-2-yl]acetyl}amino)-4-methylvaleric acid.

EXAMPLE C-8

The procedure of Example C-7 was repeated to obtain the following compounds.

TABLE 70

R^(1h) R¹³ R² k Ac-Gln-Leu Leu-Ala-Leu-OH CH₂CH₂CO₂CH₂C₆H₅ 1 Ac-Gln Leu-Ala-Leu-OH CH₂CH₂CO₂CH₂C₆H₅ 1 Ac-Arg OH CH₂C₆H₅ 1 4-ClC₆H₄CHCHCO OH CH₂C₆H₅ 1 4-H₂N(HN)CC₆H₄CO OH CH₂C₆H₅ 1 4-ClC₆H₄CHCHCO Leu-OH CH₂C₆H₅ 1 4-H₂N(HN)CC₆H₄CO Leu-OH CH₂C₆H₅ 1 4-H₂N(HN)CC₆H₄CO Leu-OH CH₂C₆H₅ 1 Ac-Arg OH H 1 4-ClC₆H₄CHCHCO OH H 1 4-H₂N(HN)CC₆H₄CO OH H 1 Ac-Arg Leu-OH H 1 4-ClC₆H₄CHCHCO Leu-OH H 1 4-H₂N(HN)CC₆H₄CO Leu-OH H 1 4-H₂N(HN)CC₆H₄CO Leu-OH H 1 4-H₂N(HN)CC₆H₄OCH₂CO OH H 1 4-H₂N(HN)CC₆H₄OCH₂CO OH CH₂C₆H₅ 1

EXAMPLE C-9

DMF was added to 157 mg (0.100 mmol) of Rink amide MBHA resin to swell the resin. Then, 2 ml of 20% piperidine/DMF solution was added and shaken for 20 minutes. After washing the resin six times with DMF, 106 mg of Fmoc-Leu-OH, 46 mg of HOBt.H₂O, 48 μL of DIPCDI and 1.5 ml of DMF were added and shaken for 90 minutes. After filtering off the liquid phase, the resin was six times washed with DMF. Then, 2 ml of 20% piperidine/DMF solution was added and shaken for 20 minutes. After washing the resin six times with DMF, 175 mg of 3-{2-{2-[(2-amino-2-oxoethyl)amino]-2-oxoethyl}-8-[(9H-fluoren-9-ylmethoxy)carbonyl]-3-oxo-1-thia-4,8-diazaspiro[4.5]decan-4-yl}-propionic acid, 46 mg of HOBt.H₂O, 48 μL of DIPCDI and 1.5 ml of DMF were added and shaken for 90 minutes. After filtering off the liquid phase, the resin was six times washed with DMF. Then, 2 ml of 20% piperidine/DMF solution was added and shaken for 20 minutes. After washing the resin six times with DMF, 106 mg of Fmoc-Leu-OH, 46 mg of HOBt.H₂O, 48 μL of DIPCDI and 1.5 ml of DMF were added and shaken for 90 minutes. After filtering off the liquid phase, the resin was washed six times with DMF. Then, 2 ml of 20% piperidine/DMF solution was added and shaken for 20 minutes. After filtering off the liquid phase, the resin was washed six times with DMF. Then, 2 ml of DMF-DCM (1:1) mixture, 0.29 ml of acetic anhydride and 0.53 ml of DIEA were added and shaken for 90 minutes. After filtering off the liquid phase, the resin was washed four times with DMF and three times with DCM. Then, 6 ml of TFA-methylene chloride (1:1) was added and shaken for 2 hours. The insoluble matter was filtered off, the filtrate was concentrated under reduced pressure, 20 ml of diethyl ether was added to the residue, and the resulting crystal was collected by filtration to obtain 55 mg of (2S)-2-{[3-(8-[(2S)-2-(acetylamino)-4-methylpentanoyl]-2-{2-[(2-amino-2-oxoethyl)amino]-2-oxoethyl}-3-oxo-1-thia-4,8-diazaspiro[4.5]decan-4-yl)propanoyl]amino}-4-methylpentanamide.

ESI-MS: m/z 626.4 for (M+H)⁺ (calcd. 625.80 for C₂₈H₄₇N₇O₇S)

EXAMPLE C-10

The procedure of Example C-9 was repeated to obtain the following compounds.

TABLE 71

R^(1h) R^(2b) R¹³ k Ac-Asp Gly-NH₂ Leu-NH₂ 1 Ac-Asn Gly-NH₂ Leu-NH₂ 1 Ac-Glu Gly-NH₂ Leu-NH₂ 1 Ac-Gln Gly-NH₂ Leu-NH₂ 1 Ac-Ser Gly-NH₂ Leu-NH₂ 1 Ac-Leu Gly-NH₂ Asp-NH₂ 1 Ac-Asp Gly-NH₂ Asp-NH₂ 1 Ac-Asn Gly-NH₂ Asp-NH₂ 1 Ac-Glu Gly-NH₂ Asp-NH₂ 1 Ac-Gln Gly-NH₂ Asp-NH₂ 1 Ac-Ser Gly-NH₂ Asp-NH₂ 1 Ac-Leu Gly-NH₂ Glu-NH₂ 1 Ac-Asp Gly-NH₂ Glu-NH₂ 1 Ac-Asn Gly-NH₂ Glu-NH₂ 1 Ac-Glu Gly-NH₂ Glu-NH₂ 1 Ac-Gln Gly-NH₂ Glu-NH₂ 1 Ac-Ser Gly-NH₂ Glu-NH₂ 1 Ac-Leu Gly-NH₂ Gln-NH₂ 1 Ac-Asp Gly-NH₂ Gln-NH₂ 1 Ac-Asn Gly-NH₂ Gln-NH₂ 1 Ac-Gln Gly-NH₂ Gln-NH₂ 1 Ac-Gln Gly-NH₂ Gln-NH₂ 1 Ac-Ser Gly-NH₂ Gln-NH₂ 1

Referential Example 1

In an atmosphere of nitrogen, 139 g of isobutyltriphenylphosphonium iodide was suspended in 350 ml of anhydrous tetrahydrofuran and cooled to −20° C. At the same temperature as above, 176 ml of 1.66 mol/L solution of n-butyllithium in hexane was dropwise added and the resulting mixture was stirred for one hour. After elevating the temperature up to the ambient temperature, 175 ml of a solution of 35.0 g of 1,4-cyclohexandione monoethylene ketal in anhydrous tetrahydrofuran was dropwise added while cooling the mixture with water. After stirring the mixture at the same temperature for one hour, the reaction mixture was poured into a mixture of ice water, aqueous solution of ammonium chloride and ethyl acetate, and the organic layer was separated. The organic layer was washed successively with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Ethyl ether was added to the residue, the deposited insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. To the residue thus obtained were added 150 ml of anhydrous tetrahydrofuran and 150 ml of 6 mol/L hydrochloric acid, and the resulting mixture was stirred at ambient temperature for 24 hours. The reaction mixture was poured into a mixture of water and ethyl acetate, and the organic layer was separated. The organic layer was washed successively with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification of the residue by column chromatography [eluent: hexane:ethyl acetate=20:1] gave 28.0 go f 4-(3-methylbutylidene)-1-cyclohexanone as a colorless oily product.

NMR (CDCl₃) δ: 0.91(6H,d,J=6.4 Hz), 1.4-2.1(3H,m), 2.44(8H,bs), 5.3-5.5(1H,m)

Referential Example 2

In 40 ml of anhydrous tetrahydrofuran were dissolved 4.00 g of 4-isopropylphenol, 5.10 g of 1,4-dioxaspiro[4.5]decan-8-ol and 8.47 g of triphenylphosphine. Then, 14.1 g of 40% solution of diethyl azodicarboxylate in toluene was dropwise added at 0-5° C., and the resulting mixture was stirred at ambient temperature for 24 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed successively with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduce pressure. Ethyl ether was added to the residue, the deposited insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The residue thus obtained was mixed with 60 ml of anhydrous tetrahydrofuran and 40 ml of 6 mol/L hydrochloric acid and stirred at ambient temperature for 24 hours. The reaction mixture was poured in a mixture of water and ethyl acetate, and the organic layer was separated. The organic layer was washed successively with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification of the residue by column chromatography [eluents: toluene:ethyl acetate=20:1, followed by hexane:ethyl acetate=20:1] gave 2.40 g of 4-(4-isopropylphenoxy)-1-cyclohexanone as a colorless oily product.

NMR (CDCl₃) δ: 1.23 (6H,d,J=6.8 Hz), 1.8-3.1(9H,m), 4.5-4.8(1H,m), 6.88(2H,d,J=8.5 Hz), 7.17(2H,d,J=8.5 Hz)

Referential Example 3

The procedure of Referential Example 1 was repeated to obtain the following compounds.

3(1)

4-(1-Methylethylidene)-1-cyclohexanone

NMR (CDCl₃) δ: 1.72(6H,s), 2.2-2.7(8H,m)

3(2)

4-Ethylidene-1-cyclohexanone

NMR (CDCl₃) δ: 1.65(3H,d,J=6.8 Hz), 2.2-3.2(8H,m), 5.41(1H,q, J=6.8 Hz)

3(3)

5-(4-Oxocyclohexylidene)-valeric acid

NMR (CDCl₃) δ: 1.5-2.8(14H,m), 5.34(1H,t,J=7.1 Hz), 9.6-10.4(1H,bs)

3(4)

4-Butylidenecyclohexanone

NMR (CDCl₃) δ: 0.7-2.7(15H,m), 5.35(1H,t,J=7.2 Hz),

3(5)

4-(2-Methylpropylidene)cyclohexanone

NMR (CDCl₃) δ: 0.98(6H,d,J=6.8 Hz), 1.5-2.8(9H,m), 5.18 (1H,d,J=9.3 Hz)

3(6)

4-(4-Methylpentylidene)cyclohexanone Referential Example 4

The procedure of Referential Example 2 was repeated to obtain the following compounds.

4(1)

4-Phenoxy-1-cyclohexanone

NMR (CDCl₃) δ: 1.9-3.0(8H,m), 4.5-4.9(1H,m), 6.8-7.5(5H,m)

4(2)

Methyl 4-[(4-oxocyclohexyl)oxy]-benzoate

NMR (CDCl₃) δ: 1.9-3.0(8H,m), 3.89(3H,s), 4.7-5.0(1H,m), 6.97(2H,d,J=9.0 Hz), 8.00(2H,d,J=9.0 Hz)

4(3)

4-[4-(Methylthio)phenoxy]-1-cyclohexanone

NMR (CDCl₃) δ: 1.9-3.0(8H,m), 2.46(3H,s), 4.5-4.8(1H,m), 6.91(2H,d,J=8.9 Hz), 7.28(2H,d,J=8.9 Hz)

4(4)

4-(4-Methoxyphenoxy)-1-cyclohexanone

NMR (CDCl₃) δ: 1.8-3.0(8H,m), 3.77(3H,s), 4.4-4.7(1H,m), 6.9-7.0 (4H,m)

4(5)

4-(2,3-Dihydro-1H-inden-5-yloxy)cyclohexanone

NMR (CDCl₃) δ: 1.8-3.1(14H,m), 4.5-4.8(1H,m), 6.6-7.0(2H,m), 7.14(1H,d,J=8 Hz)

Referential Example 5

In 50 ml of methylene chloride was dissolved 2.50 g of 4-[4-(methylthio)phenoxy]-1-cyclohexanone. After adding 5.48 g of m-chloroperbenzic acid at 0-5° C., the resulting mixture was stirred at ambient temperature for 4 hours. The reaction mixture was poured into water, pH was adjusted to 8.0 with saturated aqueous solution of sodium hydrogen carbonate, and the organic layer was separated. The organic layer thus obtained was washed successively with aqueous solution of sodium thiosulfate, water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Recrystallization of the residue from ethanol gave 2.05 g of 4-[4-(methylsulfonyl)phenoxy]-1-cyclohexanone as a colorless crystalline product.

NMR (CDCl₃) δ: 2.0-3.0(8H,m), 3.06(3H,s), 4.7-5.0(1H,m), 7.10 (2H,d,J=9.0 Hz), 7.90(2H,d,J=9.0 Hz)

Referential Example 6

In 21 ml of anhydrous tetrahydrofuran were dissolved 1.50 g of 5-(4-oxocyclohexylidene)-valeric acid and 1.17 ml of triethylamine. Then, 4.50 ml of a solution of 0.80 ml of ethyl chloroformate in anhydrous tetrahydrofuran was dropwise added at −20° C., and the resulting mixture was stirred at the same temperature as above for one hour. Then, 4.50 ml of a solution of anhydrous tetrahydrofuran containing 2.00 ml of diethylamine was dropwise added at the same temperature, and the resulting mixture was stirred at ambient temperature for one hour. The reaction mixture was poured into ice water, pH was adjusted to 2.0 with 2 mol/L hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water, saturated aqueous solution of sodium hydrogen carbonate and saturate aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification of the residue by column chromatography [eluent: toluene:ethyl acetate=1:1] gave 1.30 g of N,N-diethyl-5-(4-oxocyclohexylidene)-valeramide as a colorless oily product.

NMR (CDCl₃) δ: 1.11(3H,t,J=7.0 Hz), 1.17(3H,t,J=7.0 Hz), 1.5-2.7(14H,m), 3.31(2H,q,J=7.0 Hz), 3.38(2H,q,J=7.0 Hz), 5.37 (1H,t,J=7.0 Hz)

Referential Example 7

The procedure of Referential Example 6 was repeated to obtain the following compounds.

7(1)

5-(4-Oxocyclohexylidene)-valeramide

NMR (CDCl₃) δ: 1.5-2.8(14H,m), 5.34(1H,t,J=7.0 Hz), 5.5-6.4(2H,m)

7(2)

Benzyl 3-{[(4-oxocyclohexyl)carbonyl]amino}-propionate

NMR (CDCl₃) δ: 1.6-2.8(11H,m), 3.4-3.7(2H,m), 5.14(2H,s), 6.1-6.5(1H,m), 7.35(5H,s)

7(3)

N-Isobutyl-2-(4-oxocyclohexyl)acetamide

NMR (CDCl₃) δ: 0.92(6H,d,J=6.6 Hz), 1.2-2.6(12H,m), 3.0-3.2(2H,m), 5.6-5.9(1H,bs)

7(4)

N,N-Dipropyl-2-(4-oxocyclohexyl)-acetamide

NMR (CDCl₃) δ: 0.7-1.0(6H,m), 1.2-2.5(15H,m), 3.1-3.4(4H,m)

Referential Example 8

In an atmosphere of nitrogen, 0.23 g of magnesium powder was suspended in 2 ml of anhydrous ethyl ether. While refluxing the suspension, a solution of 2.00 g of 4-tert-butyl-1-bromobenzene in 10 ml anhydrous ethyl ether was dropwise added. After stirring the resulting mixture under reflux for one hour, a solution of 1.17 g of 1,4-cyclohexandione monoethylene ketal in 10 ml anhydrous tetrahydrofuran was dropwise added at 0-5° C., and the temperature was elevated to ambient temperature. After stirring the mixture at the same temperature as above, the reaction mixture was poured into a mixture of water and acetic acid, stirred at ambient temperature for 20 minutes, and extracted with ethyl acetate. The organic layer was washed successively with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification of the residue by column chromatography [eluent: hexane:ethyl acetate=3:1] gave 1.25 of 8-[4-(tert-butyl)phenyl]-1,4-dioxaspiro[4.5]decan-8-ol as a light yellow oily product.

NMR (CDCl₃) δ: 1.31(9H,s), 1.5-2.3(9H,m), 3.97(4H,s), 7.3-7.6(4H,m)

Referential Example 9

In 10 ml of tetrahydrofuran was dissolved 1.10 g of 8-[4-(tert-butyl)phenyl]-1,4-dioxaspiro[4.5]decane-8-ol. Then, 5.00 ml of 6 mol/L hydrochloric acid and 5.00 ml of water were added at an ice-cooled temperature and the resulting mixture was stirred at ambient temperature for 2 hours. The reaction mixture was poured into a mixture of water and ethyl acetate, and the organic layer was separated. The organic layer was washed successively with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Hexane was added to the residue, and the resulting crystal was collected by filtration to obtain 0.67 g of 4-[4-(tert-butyl)phenyl]-4-hydroxy-1-cyclohexanone as a colorless crystalline product.

NMR (CDCl₃) δ: 1.32(9H,s), 2.0-2.5(7H,m), 2.6-3.2(2H,m), 7.43(4H,s)

Referential Example 10

In 75 ml of benzene was dissolved 15.0 g of 2-ethylbutanal, to which were added 10.5 g of 3-buten-2-one and 0.15 ml of concentrated sulfuric acid at ambient temperature. While heating the mixture under reflux, an azeotropic distillation treatment was carried out for 3 hours by means of Dean Stark apparatus. The reaction mixture was poured into a mixture of ice water and ethyl acetate, pH was adjusted to 7.0 with a saturated aqueous solution of sodium hydrogen carbonate, and the organic layer was separated. The organic layer was washed successively with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification of the residue by distillation under reduced pressure gave 4.90 g of 4,4-diethyl-2-cyclohexen-1-one as a light yellow oily product.

NMR (CDCl₃) δ: 0.89(6H,t,J=7.3 Hz), 1.85(2H,t,J=6.8 Hz), 1.4-1.8(4H,m), 2.44(2H,t,J=6.8 Hz), 5.92(1H,d,J=10.3 Hz), 6.72(1H,d,J=10.3 Hz)

Referential Example 11

In 22 ml of acetic acid was dissolved 2.20 g of 4,4-diethyl-2-cyclohexen-1-one, to which was added 0.22 g of 5% palladium-carbon. Under a pressure of 5 atmospheres, the mixture was stirred at ambient temperature for one hour under a stream of hydrogen. The reaction mixture was filtered, and the solvent was distilled off under reduced pressure. Purification of the residue by column chromatography [eluent: hexane:ethyl acetate=10:1] gave 1.90 g of 4,4-diethyl-1-cyclohexanone as a colorless oily product.

NMR (CDCl₃) δ: 0.84(6H,t,J=7.3 Hz), 1.2-1.8(8H,m), 2.32(4H,t,J=6.8 Hz)

Referential Example 12

In an atmosphere of nitrogen, 280 ml of anhydrous tetrahydrofuran was added to 23.0 g of sodium hydride, to which was dropwise added a solution of 40.0 g of diethyl malonate in 80 ml of anhydrous tetrahydrofuran furan at 40° C. over a period 30 minutes. After stirring the mixture at the same temperature as above for one hour, the mixture was cooled to 15° C., and a solution of 52.5 g of ethyl acrylate in 80 ml of anhydrous tetrahydrofuran was dropwise added thereto over a period of 30 minutes. After a reaction at 45° C. for 30 minutes followed by cooling, the reaction mixture was poured into a mixture of ice water and ethyl acetate. After adjusting pH value to 2.0 with 6 mol/L hydrochloric acid, the organic layer was separated. The organic layer was washed successively with water, saturated aqueous solution of sodium hydrogen carbonate and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. Purification of the residue by distillation under reduced pressure gave 61.8 g of 2,4,4-tricarbethoxy-cyclohexanone as a light yellow oily product.

Boiling point: 140-153° C. (2.0-2.5 mmHg)

Referential Example 13

To 540 ml of dimethyl sulfoxide were added 21.9 g of lithium chloride, 13.9 ml of pyridine and 9.3 ml of water, and the resulting mixture was gently heated under reflux. While refluxing the mixture, 100 ml of a solution of 54.0 g of 2,4,4-tricarbethoxy-cyclohexanone in dimethyl sulfoxide was dropwise added thereto over one hour. After a reaction at the same temperature as above for 2 hours, the mixture was cooled and poured into a mixture of ice water and ethyl acetate, and the organic layer was separated. The organic layer was washed with saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification of the residue by distillation under reduced pressure gave 13.5 g of 4-carbethoxycyclohexanone as a light yellow oily product.

Boiling point: 103-107° C. (2.5-3.5 mmHg)

Referential Example 14

In 120 ml of methylene chloride was suspended 6.0 g of 4-(methoxycarbonyl)-benzoic acid, to which were added 3.5 ml of oxalyl chloride and 0.05 ml of N,N-dimethylformamide at 0-5° C. After a reaction at the same temperature as above for 3 hours, the mixture was stirred at ambient temperature for 24 hours. Then, a 90.7 g portion of the reaction mixture was taken out, and 6.9 ml of diethylamine was added thereto. The mixture was stirred at ambient temperature for 3 hours, and then poured into ice water. pH was adjusted to 1.0 with 6 mol/L hydrochloric acid, and the organic layer was separated. The organic layer was washed successively with water, saturated aqueous solution of sodium hydrogen carbonate and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Thus, 5.89 g of methyl 4-[(diethylamino)carbonyl]-benzoate was obtained as a red oily product.

Referential Example 15

In 25 ml of methanol was dissolved 5.44 g of methyl 4-[(diethylamino)carbonyl]-benzoate. After adding 25 ml of 1 mol/L aqueous solution of sodium hydroxide at 0-5° C., the mixture was stirred at ambient temperature for 2 hours. The reaction mixture was poured into a mixture of water and ethyl acetate, and the aqueous layer was separated. The aqueous layer was mixed with ethyl acetate, pH was adjusted to 1.5 with 6 mol/L hydrochloric acid, and the organic layer was separated. The organic layer was washed successively with water and saturated aqueous solution of sodium chloride and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. Diisopropyl ether was added to the residue, and the deposited crystal was collected by filtration to obtain 2.94 g of 4-[(diethylamino)carbonyl]-benzoic acid as a colorless crystalline product.

Referential Example 16

In 2.3 ml of methylene chloride was added 0.470 g of 5-phenylvaleric acid, to which were added at ambient temperature 0.287 ml of thionyl chloride and 0.020 ml of N,N-dimethylformamide. After a reaction at the same temperature as above for 4 hours, the reaction mixture was concentrated under reduced pressure, 5.0 ml of toluene was added and the resulting mixture was further concentrated under reduced pressure. Thus, 0.510 g of 5-phenylvaleric acid chloride was obtained as a light yellow oily product.

Referential Example 17

In 20 ml of N,N-dimethylformamide was suspended 1.11 g of 60% sodium hydride, to which was dropwise added 5.0 ml of ethyl diethylphosphonoacetate over 5 minutes at an ice-cooled temperature. The resulting mixture was stirred at ambient temperature for 90 minutes. Then, 2.49 ml of isovalerylaldehyde was dropwise added at an ice-cooled temperature over a period of 5 minutes, and the resulting mixture was stirred at ambient temperature for one hour. The reaction mixture was poured into a mixture of chloroform and water, pH was adjusted to 1.0 with 2 mol/L hydrochloric acid, and the organic layer was separated. The organic layer was washed successively with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification of the residue by silica gel column chromatography [eluent: n-hexane:ethyl acetate=10:1] gave 3.27 g of ethyl (E)-5-methyl-2-hexenoate as a colorless oily product.

NMR (CDCl₃) δ: 0.93(6H,d,J=6.3 Hz), 1.29(3H,t,J=7.1 Hz), 1.5-1.9((1H,m), 2.0-2.3(2H,m), 4.19(2H,q,J=7.1 Hz), 5.7-5.9(1H,m), 6.9-7.0(1H,m)

Referential Example 18

In 15 ml of ethanol was dissolved ethyl (E)-5-methyl-2-hexenoate, to which was added 0.50 g of 5% palladium-carbon. Under a stream of hydrogen, the mixture was stirred at ambient temperature for 2 hours. The reaction mixture was filtered with Celite, and the solvent was distilled off under reduced pressure. Thus, 2.2 g of ethyl 5-methylhexanoate was obtained as a colorless oily product.

NMR (CDCl₃) δ: 0.88(6H,d,J=6.3 Hz), 1.1-2.1(8H,m), 2.28(2H,t,J=7.4 Hz), 4.12(2H,q,J=7.2 Hz)

Referential Example 19

In 20 ml of ethanol was dissolved 2.0 g of ethyl 5-methylhexanoate. After adding 10 ml of 2 mol/L aqueous solution of sodium hydroxide at ambient temperature, the resulting mixture was stirred for 30 minutes. The ethanol was distilled off under reduced pressure, the residue was poured into a mixture of water and chloroform, pH was adjusted to 1.0 with 2 mol/L hydrochloric acid, and the organic layer was separated. The organic layer was washed successively with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Diisopropyl ether was added to the residue, and the deposited crystal was collected by filtration. Thus, 1.56 g of 5-methylhexanoic acid was obtained as a colorless oily product.

NMR (CDCl₃) δ: 0.89(6H,d,J=6.1 Hz), 1.1-2.1(5H,m), 2.34(2H,t,J=7.3 Hz)

Referential Example B-1

In 200 ml of toluene were dissolved 20.00 g of tert-butyl 4-oxo-1-piperidinecarboxylate and 12.6 ml of β-phenethylamine. After stirring the resulting solution at ambient temperature for 30 minutes, 15.07 g of mercaptosuccinic acid was added, and the resulting mixture was subjected to an azeotropic distillation treatment under reflux for 6 hours. The reaction mixture was poured into a mixture of ice water and ethyl acetate, and the organic layer was separated. The organic layer was washed successively with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification of the residue by column chromatography [eluent: toluene:ethyl acetate=5:1] gave 22.10 g of 2-[8-(tert-butoxycarbonyl)-3-oxo-4-phenethyl-1-thia-4,8-diazaspiro[4.5]decan-2-yl]-acetic acid as a yellow oily product.

NMR (CDCl₃) δ: 1.47(9H,s), 1.4-2.2(4H,m), 2.4-3.8(8H,m), 3.8-4.4(3H,m), 7.1-7.4(6H,m)

Referential Example B-2

The procedure of Referential Example B-1 was repeated to obtain the compounds listed in Table 72.

TABLE 72

No. X R² 2 (1)

2 (2)

2 (3)

-CH₂CH₂CH₂CH₃ 2 (4)

-CH₂CH₂OCH₃ 2 (5) -COCH₃

2 (6)

2 (7)

H 2 (8)

Properties of the compounds of Table 72 are as mentioned below.

B-2(1)

NMR (CDCl₃) δ: 1.1-2.3 (4H,m), 1.46 (9H,s), 2.3-3.8 (8H,m), 3.8-4.4 (3H,m), 5.12 (2H,s), 6.0-6.7 (1H,bs), 7.0-7.2 (5H,m)

B-2(2)

NMR (CDCl₃) δ: 1.44 (9H,s), 1.5-2.2 (4H,m), 2.6-3.5 (4H,m), 3.9-4.3 (3H,m), 4.48 (1H,d,J=16.8 Hz), 4.69 (1H,d,J=16.8 Hz), 7.27 (5H,s), 9.13 (1H,bs)

B-2(3)

NMR (CDCl₃) δ: 0.92 (3H,t,J=7.2 Hz), 1.1-2.3 (8H,m), 1.47 (9H,s), 2.3-3.6 (6H,m), 3.9-4.4 (3H,m), 6.0-6.4 (1H,bs)

B-2(4)

NMR (CDCl₃) δ: 1.2-2.3 (4H,m), 1.46 (9H,s), 2.5-3.7 (8H,m), 3.47 (3H,s), 4.0-4.4 (3H,m), 5.9-6.5 (1H,bs)

B-2(5)

NMR (CDCl₃) δ: 2.12 (3H,s), 1.6-2.2 (4H,m), 2.5-4.0 (9H,m), 4.14 (1H,dd,J=3.9 Hz,8.8 Hz), 4.6-4.9 (1H,m), 5.12 (2H,s), 6.4 (1H,bs), 7.3-7.6 (5H,s)

B-2(7)

NMR (d₆-DMSO) δ: 1.39 (9H,s), 1.4-2.2 (4H,m), 2.3-3.5 (4H,m), 3.5-4.2 (2H,m), 4.04 (1H,dd,J=3.8 Hz,9.9 Hz), 8.89 (1H,s), 12.48 (1H,bs)

B-2(8)

NMR (CDCl₃) δ: 0.93 (6H,d,J=5.9 Hz), 1.0-2.4 (7H,m), 1.47 (9H,s), 2.5-3.5 (6H,m), 4.0-4.4 (3H,m), 6.2-6.8 (1H,bs)

Referential Example B-3

In 200 ml of N,N-dimethylformamide was dissolved 22.0 g of 2-[8-(tert-butoxycarbonyl)-3-oxo-4-phenethyl-1-thia-4,8-diazaspiro[4.5]decan-2-yl]-acetic acid. After adding 8.40 g of anhydrous potassium carbonate at 0-5° C., 4.90 ml of ethyl iodide was dropwise added over a period of 5 minutes. The resulting mixture was stirred at the same temperature as above for 10 minutes and then at ambient temperature for 2 hours, the reaction mixture was poured into a mixture of ice water and ethyl acetate, pH was adjusted to 2.0 with 6 mol/L hydrochloric acid, and the organic layer was separated. The organic layer was washed successively with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification of the residue by column chromatography [eluent: hexane:ethyl acetate=2:1] gave 19.85 g of tert-butyl 2-(2-ethoxy-2-oxoethyl)-3-oxo-4-phenethyl-1-thia-4,8-diazaspiro]4.5]decane-8-carboxylate as a yellow oily product.

NMR (CDCl₃ δ: 1.47(9H,s), 1.28(3H,t,J=7.2 Hz), 1.4-2.2(4H,m), 2.5-3.6(8H,m), 4.0-4.4(5H,m), 7.27(5H,s)

Referential Example B-4

The procedure of Referential Example B-3 was repeated to obtain the following compound:

tert-Butyl 2-(2-ethoxy-2-oxoethyl)-4-isopentyl-3-oxo-1-thia-4,8-diazaspiro[4.5]decan-8-carboxylate

NMR (CDCl₃) δ: 0.93(6H,d,J=5.9 Hz), 1.0-3.4(13H,m), 1.27(3H,t,J=7.1 Hz), 1.47(9H,s), 3.9-4.4(5H,m)

Referential Example B-5

In 56 ml of methylene chloride was dissolved 18.50 g of tert-butyl 2-(2-ethoxy-2-oxoethyl)-3-oxo-4-phenethyl-1-thia-4,8-diazaspiro[4.5]decane-8-carboxylate. After adding 56 ml of trifluoroacetic acid at 0-5° C., the resulting mixture was stirred at the same temperature as above for 30 minutes and then at ambient temperature for 5 hours. The solvent was distilled off under reduced pressure, the residue was poured into a mixture of ice water and ethyl acetate, pH was adjusted to 8.0 with saturated aqueous solution of sodium hydrogen carbonate, and the organic layer was separated. The organic layer was washed successively with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. Thus, 7.26 g of ethyl 2-(3-oxo-4-phenethyl-1-thia-4,8-diazaspiro[4.5]decan-2-yl)-acetate was obtained as a yellow oily product.

NMR (CDCl₃) δ: 1.29(3H,t,J=7.0 Hz), 1.2-1.8(2H,m), 2.2-3.6(13H,m), 4.0-4.4(3H,m), 7.25(5H,s)

Referential Example B-6

The procedure of Referential Example B-5 was repeated to obtain the following compounds.

B-6(1)

Trifluoroacetic acid salt of 2-(4-benzyl-3-oxo-1-thia-4,8-diazaspiro[4.5]decan-2-yl)-acetic acid

NMR (d₆-DMSO) δ: 1.6-2.0(2H,m), 2.2-3.6(8H,m), 4.32(1H,dd,J=3.9 Hz, 9.5 Hz), 4.44(1H,d,J=16.5 Hz), 4.68(1H,d,J=16.5 Hz), 7.29(5H,s), 8.6-9.1(2H,bs)

B-6(2)

Ethyl 2-(4-isopentyl-3-oxo-1-thia-4,8-diazaspiro[4.5]deecan-2-yl)-acetate

NMR (CDCl₃) δ: 0.93(6H,d,J=5.6 Hz), 1.27(3H,t,J=7.2 Hz), 1.4-3.4(16H,m), 4.0-4.4(3H,m)

Referential Example B-7

In 5 ml of methylene chloride was dissolved 0.50 g of ethyl 2-(3-oxo-4-phenethyl-1-thia-4,8-diazaspiro[4.5]decan-2-yl)-acetate. After adding 0.25 ml of triethylamine at 0-5° C., 0.26 ml of ethyl succinyl chloride was dropwise added. After stirring at ambient temperature for 5 hours, the reaction mixture was poured into ice water, pH was adjusted to 2.0 with 2 mol/L hydrochloric acid, and the organic layer was separated. The organic layer was washed successively with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification of the residue by column chromatography [eluent: hexane:ethyl acetate=1:1] gave 0.65 g of ethyl 4-[2-(2-ethoxy-2-oxoethyl)-3-oxo-4-phenethyl-1-thia-4,8-diazaspiro[4.5]decan-8-yl]-4-oxobutanoate as a yellow oily product.

NMR (CDCl₃) δ: 1.26(3H,t,J=7.1 Hz), 1.29(3H,t,J=7.1 Hz), 1.2-2.5(4H,m), 2.6-5.0(19H,m), 7.26(5H,s)

Referential Example B-8

The procedure of Referential Example B-7 was repeated to obtain the compounds listed in Table 73.

TABLE 73

No. R^(1h) R² 8 (1)

8 (2)

8 (3)

8 (4)

8 (5)

8 (6) -COCH₂CH₂COOEt

8 (7)

Properties of the compounds of Table 73 are as follows.

B-8(1)

NMR (CDCl₃) δ: 1.24 (3H,t,J=7.0 Hz), 1.2-2.0 (4H,m), 2.5-4.9 (11H,m), 3.73 (2H,s), 4.14 (2H,q,J=7.0 Hz), 7.0-7.8 (10H,m)

B-8(2)

NMR (CDCl₃) δ: 1.28 (3H,t,J=7.1 Hz), 1.5-2.2 (6H,m), 2.2-4.0 (13H,m), 4.0-4.9 (4H,m),7.0-7.4 (10H,m)

B-8(3)

NMR (CDCl₃) δ: 1.29 (3H,t,J=7.0 Hz), 1.5-2.3 (4H,m), 2.5-3.8 (8H,m), 4.0-4.9 (5H,m), 6.86 (1H,d,J=15.4 Hz), 7.1-7.7 (10H,m), 7.69 (1H,d,J=15.4 Hz)

B-8(5)

NMR (CDCl₃) δ: 0.93 (6H,d,J=5.6 Hz), 1.28 (3H,t,J=7.2 Hz), 1.2-3.6 (17H,m), 2.10 (3H,s), 4.0-4.4 (4H,m), 4.5-5.2 (2H,m), 5.4-7.0 (3H,m)

B-8(6)

NMR (CDCl₃) δ: 0.93 (6H,d,J=5.8 Hz), 1.27 (6H,t,J=7.1 Hz), 1.1-2.4 (7H,m), 2.5-3.7 (10H,m), 3.8-4.9 (7H,m)

B-8(7)

NMR (CDCl₃) δ: 1.26 (3H,t,J=7.2 Hz), 1.4-2.2 (2H,m), 2.18 (3H,s), 2.4-4.9 (13H,m), 4.17 (2H,q,J=7.2 Hz), 6.21 (1H,s), 7.0-7.6 (10H,m)

Referential Example C-1

Using 9H-fluoren-9-ylmethyl 4-oxo-1-piperidinecarboxylate, the procedure of Referential Example B-1 was repeated to obtain 2-{4-[3-(tert-butoxy) -3-oxopropyl]-8-[(9H-fluoren-9-ylmethoxy)carbonyl]-3-oxo-1-thia-4,8-diazaspiro[4.5]decan-2-yl}-acetic acid.

Referential Example C-2

The procedure of Example 38 was repeated to obtain 9H-fluoren-9-ylmethyl 2-{2-[(2-amino-2-oxoethyl)amino]-2-oxoethyl}-4-[3-(tert-butoxy)-3-oxopropyl]-3-oxo-1-thia-4,8-diazaspiro[4.5]decan-8-carboxylate.

Referential Example C-3

The procedure of Example 5 was repeated to obtain 3-{2-{2-[(2-amino-2-oxoethyl)amino]-2-oxoethyl}-8-[(9H-fluoren-9-ylmethoxy)carbonyl]-3-oxo-1-thia-4,8-diazaspiro[4.5]decan-4-yl}-propionic acid.

Referential Example C-4

The procedure of Example 15 was repeated to obtain (3R)-8-(tert-butoxycarbonyl)-1-thia-4,8-diazaspiro[4.5]decane-3-carboxylic acid.

Referential Example C-5

The procedure of Example 17 was repeated to obtain (3R)-4-benzoyl-8-(tert-butoxycarbonyl)-1-thia-4,8-diazaspiro[4.5]decane-3-carboxylic acid.

Referential Example C-6

The procedure of Referential Example B-5 was repeated to obtain (3R)-4-benzoyl-1-thia-4,8-diazaspiro[4.5]decane-3-carboxylic acid.

Referential Example C-7

Using 9-fluorenylmethyloxycarbonyl-N-hydroxy-succinimide, the procedure of Referential Example B-7 was repeated to obtain (3R)-4-benzoyl-8-[(9H-fluoren-9-ylmethoxy)carbonyl]-1-thia-4,8-diazaspiro[4.5]decane-3-carboxylic acid.

Industrial Utilizability

The compounds of the present invention exhibit an AP-1 activity-inhibitory action and, based on the AP-1 inhibitory action thereof, suppress the expression of a wide variety of genes and are useful as an agent for treating and preventing autoimmune diseases with lessened side reactions. 

What is claimed is:
 1. A spiro compound represented by the following general formula:

wherein A represents a group of the following general formula:

wherein R^(1a) represents a hydrogen atom, a halogen atom, a cyano group, a nitro group, an unprotected or protected carboxyl group, an unprotected or protected hydroxyl group or an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl, aralkyl, alkoxy, aryloxy, acyl, alkoxycarbonyl, aryloxycarbonyl, carbamoyl, amino or heterocyclic group; and Y represents an oxygen atom, a sulfur atom, an unsubstituted or substituted imino group, a carbonyl group, a vinylene group, a sulfinyl group, a sulfonyl group or a group —CH(OH)—; a group of the following general formula:

wherein R^(1b) represents a halogen atom, a cyano group, a nitro group, an unprotected or protected carboxyl group, an unprotected or protected hydroxyl group, a substituted alkyl group, or an unsubstituted or substituted alkenyl, cycloalkyl, aryl, aralkyl, alkoxy, aryloxy, acyl, alkoxycarbonyl, aryloxycarbonyl, carbamoyl, amino or heterocyclic group; a group of the following general formula:

wherein R^(1c) and R^(1d), which may be the same or different, each represent a hydrogen atom, a halogen atom, a cyano group, a nitro group, an unprotected or protected carboxyl group, an unprotected or protected hydroxyl group, a mercapto group, or an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl, aralkyl, alkoxy, aryloxy, acyl, alkoxycarbonyl, aryloxycarbonyl, carbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, amino or heterocyclic group; a group of the following general formula:

wherein R^(1e) and R^(1f), which may be the same or different, each represent a halogen atom, a cyano group, a nitro group, an unprotected or protected carboxyl group, an unprotected or protected hydroxyl group, or an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl, aralkyl, alkoxy, aryloxy, acyl, alkoxycarbonyl, aryloxycarbonyl, carbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, amino or heterocyclic group; or a group of the following general formula:

wherein R^(1g) represents an unsubstituted or substituted heterocyclic group; R² represents a hydrogen atom, a formyl group, an alkanoyl group, an aralkylcarbonyl group, or an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aroyl, heterocyclic carbonyl, aryl, aralkyl, alkylsulfonyl, arylsulfonyl or heterocyclic group; R³ and R⁴, which may be the same or different, each represent a hydrogen atom, a halogen atom, a cyano group, an unprotected or protected carboxyl group, an unprotected or protected hydroxyl group or an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, acyl, alkoxycarbonyl, aryl, amino, alkylamino, acylamino, carbamoyl or heterocyclic group, or a group of the following general formula: —(CH₂)_(m)—CO—(D)_(p)R⁷ wherein D represents an amino acid residue, R⁷ represents a hydroxyl group or an amino group, p is 1, 2 or 3, and m is 0, 1, 2, or 3, or alternatively, R³ and R⁴, taken conjointly, represent an oxo group; R⁵ and R⁶, which may be the same or different, each represent a hydrogen atom, a halogen atom, a cyano group, an unprotected or protected carboxyl group, an unprotected or protected hydroxyl group, an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, acyl, alkoxycarbonyl, aryl, amino, alkylamino, acylamino, carbamoyl or heterocyclic group, or alternatively, R⁵ and R⁶, taken conjointly with the terminal carbon atom to which R⁵ and R⁶ are connected, represent an alkenyl group; and n represents 0, 1 or 2; and salts of these spiro compounds.
 2. A spiro compound represented by the following general formula:

wherein A represents a group of the following general formula:

wherein R^(1a) represents a hydrogen atom, a halogen atom, a cyano group, a nitro group, an unprotected or protected carboxyl group, an unprotected or protected hydroxyl group, or an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl, aralkyl, alkoxy, aryloxy, acyl, alkoxycarbonyl, aryloxycarbonyl, carbamoyl, amino or heterocyclic group; and Y represents an oxygen atom, a sulfur atom, an unsubstituted or substituted imino group, carbonyl group, a vinylene group, a sulfinyl group, a sulfonyl group or a group —CH(OH)—; a group of the following general formula:

wherein R^(1b) represents a halogen atom, a cyano group, a nitro group, an unprotected or protected carboxyl group, an unprotected or protected hydroxyl group, a substituted alkyl group, or an unsubstituted or substituted alkenyl, cycloalkyl, aryl, aralkyl, alkoxy, aryloxy, acyl, alkoxycarbonyl, aryloxycarbonyl, carbamoyl, amino or heterocyclic group; a group of the following general formula:

wherein R^(1c) and R^(1d), which may be the same or different, each represent a hydrogen atom, a halogen atom, a cyano group, a nitro group, an unprotected or protected carboxyl group, an unprotected or protected hydroxyl group, a mercapto group, or an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl, aralkyl, alkoxy, aryloxy, acyl, alkoxycarbonyl, aryloxycarbonyl, carbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, amino or heterocyclic group; a group of the following formula:

wherein R^(1e) and R^(1f), which may be the same or different, each represent a halogen atom, a cyano group, a nitro group, an unprotected or protected carboxyl group, an unprotected or protected hydroxyl group, or an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl, aralkyl, alkoxy, aryloxy, acyl, alkoxycarbonyl, aryloxycarbonyl, carbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, amino or heterocyclic group; or a group of the following general formula;

wherein R^(1g) represents an unsubstituted or substituted heterocyclic group; R² represents a hydrogen atom, a formyl group, an alkanoyl group, an aralkylcarbonyl group, or an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aroyl, heterocyclic carbonyl, aryl, aralkyl, alkylsulfonyl, arylsulfonyl or heterocyclic group; R³ and R⁴, which may be the same or different, each represent a hydrogen atom, a halogen atom, a cyano group, an unprotected or protected carboxyl group, an unprotected or protected hydroxyl group, or an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, acyl, alkoxycarbonyl, aryl, amino, alkylamino, acylamino, carbamoyl or heterocyclic group, or alternatively, R³ and R⁴, taken conjointly, represent an oxo group; R⁵ and R⁶, which may be the same or different, each represent a hydrogen atom, a halogen atom, a cyano group, an unprotected or protected carboxyl group, an unprotected or protected hydroxyl group, an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, acyl, alkoxycarbonyl, aryl, amino, alkylamino, acylamino, carbamoyl or heterocyclic group, or alternatively, R⁵ and R⁶, taken conjointly with the terminal carbon atom to which R⁵ and R⁶ are combined, represent an alkenyl group; and n represents 0, 1 or 2; or a salt thereof.
 3. A spiro compound or a salt thereof according to claim 2, wherein A represents a group of the following general formula:

wherein R^(1aa) represents an unsubstituted or substituted alkyl, alkenyl, aryl or heterocyclic group; and Y¹ represents an oxygen atom or a vinylene group; a group of the following general formula:

wherein R^(1ba) represents a substituted alkyl group or an unsubstituted or substituted alkenyl, aryl or heterocyclic group; a group of the following general formula:

wherein R^(1ca) and R^(1da), which may be the same or different, each represent a hydrogen atom, an unsubstituted or substituted alkyl, alkenyl, aryl or heterocyclic group; or a group of the following general formula:

wherein R^(1ea) and R^(1fa), which may be the same or different, each represent an unprotected or protected hydroxyl group, or an unsubstituted or substituted aryl group; R² represents a hydrogen atom, a formyl group, an alkanoyl group, an aralkylcarbonyl group, or an unsubstituted or substituted alkyl, alkenyl, aroyl, heterocyclic carbonyl, aryl, aralkyl or heterocyclic group; R³ and R⁴, which may be the same or different, each represent a hydrogen atom, an unsubstituted or substituted alkoxycarbonyl or carbamoyl group, or a group of the following general formula: —(CH₂)_(m)—CO—(D)_(p)—R⁷ wherein D represents an amino acid residue; R⁷ represents a hydroxyl group or an amino group; p represents 1, 2 or 3; and m represents 0, 1, 2 or 3; or alternatively, R³ and R⁴, taken conjointly, represent an oxo group; R⁵ and R⁶, which may be the same or different, each represent a hydrogen atom or an unsubstituted or substituted alkyl group; and n represents 0 or
 2. 4. A pharmaceutical composition comprising a spiro compound or a salt thereof according to any one of claim 1 or
 2. 5. A pharmaceutical composition comprising a spiro compound or a salt thereof according to any one of claim 1 or 2 wherein said spiro compound or salt thereof is an AP-1 inhibitor.
 6. A pharmaceutical composition comprising a spiro compound represented by the following general formula:

wherein A^(o) represents a group of the following general formula:

wherein R^(1a) represents a hydrogen atom, a halogen atom, a cyano group, a nitro group, an unprotected or protected carboxyl group, an unprotected or protected hydroxyl group, or an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl, aralkyl, alkoxy, aryloxy, acyl, alkoxycarbonyl, aryloxycarbonyl, carbamoyl, amino or heterocyclic group; and Y⁰ represents an oxygen atom, sulfur atom, an unsubstituted or substituted imino group, a carbonyl group, a methylene group, a vinylene group, a sulfinyl group, a sulfonyl group or a group —CH(OH)—; a group of the following general formula:

wherein R^(1c) and R^(1d), which may be the same or different, each represent a hydrogen atom, a halogen atom, a cyano group, a nitro group, an unprotected or protected carboxyl group, an unprotected or protected hydroxyl group, a mercapto group, or an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl, aralkyl, alkoxy, aryloxy, acyl, alkoxycarbonyl, aryloxycarbonyl, carbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, amino or heterocyclic group; a group of the following general formula:

wherein R^(1e) and R^(1f), which may be the same or different, each represent a halogen atom, a cyano group, a nitro group, an unprotected or protected carboxyl group, an unprotected or protected hydroxyl group, or an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl, aralkyl, alkoxy, aryloxy, acyl, alkoxycarbonyl, aryloxycarbonyl, carbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, amino or heterocyclic group; or a group of the following general formula:

wherein R^(1g) represents an unsubstituted or substituted heterocyclic group; R^(2a) represents a hydrogen atom or an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, acyl, aryl, aralkyl, alkylsulfonyl, arylsulfonyl or heterocyclic group; R³ and R⁴, which may be the same or different, each represent a hydrogen atom, a halogen atom, a cyano group, an unprotected or protected carboxyl group, an unprotected or protected hydroxyl group, or an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, acyl, alkoxycarbonyl, aryl, amino, alkylamino, acylamino, carbamoyl or heterocyclic group, or alternatively, R³ and R⁴, taken conjointly, represent an oxo group; R⁵ and R⁶, which may be the same or different, each represent a hydrogen atom, a halogen atom, a cyano group, an unprotected or protected carboxyl group, an unprotected or protected hydroxyl group, an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, acyl, alkoxycarbonyl, aryl, amino, alkylamino, acylamino, carbamoyl or heterocyclic group, or alternatively, R⁵ and R⁶, taken conjointly with the terminal carbon atom to which R⁵ and R⁶ are connected, represent an alkenyl group; and n represents 0, 1 or 2; or a salt thereof.
 7. A pharmaceutical composition comprising a spiro compound represented by the following general formula:

wherein A⁰ represents a group of the following general formula:

wherein R^(1a) represents a hydrogen atom, a halogen atom, a cyano group, a nitro group, an unprotected or protected carboxyl group, an unprotected or protected hydroxyl group, or an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl, aralkyl, alkoxy, aryloxy, acyl, alkoxycarbonyl, aryloxycarbonyl, carbamoyl, amino or heterocyclic group; and Y⁰ represents an oxygen atom, a sulfur atom, an unsubstituted or substituted imino group, a carbonyl group, a methylene group, a vinylene group, a sulfinyl group, a sulfonyl group or a group —CH(OH)—; a group of the following general formula:

wherein R^(1c) and R^(1d), which may be the same or different, each represent a hydrogen atom, a halogen atom, a cyano group, a nitro group, an unprotected or protected carboxyl group, an unprotected or protected hydroxyl group, a mercapto group, or an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl, aralkyl, alkoxy, aryloxy, acyl, alkoxycarbonyl, aryloxycarbonyl, carbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, amino or heterocyclic group; a group of the following general formula:

wherein R^(1e) and R^(1f), which may be the same or different, each represent a halogen atom, a cyano group, a nitro group, an unprotected or protected carboxyl group, an unprotected or protected hydroxyl group, or an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl, aralkyl, alkoxy, aryloxy, acyl, alkoxycarbonyl, aryloxycarbonyl, carbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, amino or heterocyclic group; or a group of the following general formula:

wherein R^(1g) represents an unsubstituted or substituted heterocyclic group; R^(2a) represents a hydrogen atom or an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, acyl, aryl, aralkyl, alkylsulfonyl, arylsulfonyl or heterocyclic group; R³ and R⁴, which may be the same or different, each represent a hydrogen atom, a halogen atom, a cyano group, an unprotected or protected carboxyl group, an unprotected or protected hydroxyl group, or an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, acyl, alkoxycarbonyl, aryl, amino, alkylamino, acylamino, carbamoyl or heterocyclic group, or alternatively, R³ and R⁴, taken conjointly, represent an oxo group; R⁵ and R⁶, which may be the same or different, each represent a hydrogen atom, a halogen atom, a cyano group, an unprotected or protected carboxyl group, an unprotected or protected hydroxyl group, an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, acyl, alkoxycarbonyl, aryl, amino, alkylamino, acylamino, carbamoyl or heterocyclic group, or alternatively, R⁵ and R⁶, taken conjointly with the terminal carbon atom to which R⁵ and R⁶ are connected, represent an alkenyl group; and n represents 0, 1 or 2; or a salt thereof, wherein said spiro compound or salt thereof is an AP-1 inhibitor.
 8. A composition comprising the compound of claim 1 or claim 2, in the form of a tablet, capsule, powder, syrup, granule, pill, suspension, emulsion, solution, powdery preparation, suppository, ointment, or injection.
 9. A method for preventing or treating an autoimmune or inflammatory disease comprising administering an effective amount of a compound of claim 1 or 2 to a subject in need thereof.
 10. A method for inhibiting AP-1 activity comprising by administering an amount of the compound of claim 1 or 2 effective to inhibit an activity of AP-1.
 11. A method for suppressing the expression of a gene through inhibition of AP-1 activity, comprising administering an effective amount of a compound of claim 1 or 2 for a time and under conditions suitable for suppressing the expression of said gene. 